Compounds, their preparation and use

ABSTRACT

The present invention relates to compounds of the general formula (I) 
                 
 
     The compounds are useful in the treatment and/or prevention of conditions mediated by nuclear receptors, in particular the Peroxisome Proliferator-Activated Receptors (PPAR).

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of application Ser. No. 09/770,896,filed on Jan. 26, 2000 now U.S. Pat. No. 6,555,577 and claims priorityunder 35 U.S.C. 119 of Danish application no. PA 2000 00136 filed onJan. 28, 2000, Danish application no. PA 2000 01071 filed on Jul. 7,2000, Danish application no. PA 2000 01594 filed on Oct. 25, 2000, U.S.provisional application No. 60/181,192 filed on Feb. 9, 2000, U.S.provisional application No. 60/217,948 filed on Jul. 13, 2000, and U.S.provisional application No. 60/245,392 filed on Nov. 2, 2000, thecontents of which are fully incorporated herein by reference.

FIELD OF INVENTION

The present invention relates to novel compounds, pharmaceuticalcompositions containing them, methods for preparing the compounds andtheir use as medicaments. More specifically, compounds of the inventioncan be utilised in the treatment and/or prevention of conditionsmediated by nuclear receptors, in particular the PeroxisomeProliferator-Activated Receptors (PPAR).

BACKGROUND OF THE INVENTION

Coronary artery disease (CAD) is the major cause of death in Type 2diabetic and metabolic syndrome patients (i.e. patients that fall withinthe ‘deadly quartet’ category of impaired glucose tolerance, insulinresistance, hypertriglyceridaemia and/or obesity).

The hypolipidaemic fibrates and antidiabetic thiazolidinedionesseparately display moderately effective triglyceride-lowering activitiesalthough they are neither potent nor efficacious enough to be a singletherapy of choice for the dyslipidaemia often observed in Type 2diabetic or metabolic syndrome patients. The thiazolidinediones alsopotently lower circulating glucose levels of Type 2 diabetic animalmodels and humans. However, the fibrate class of compounds are withoutbeneficial effects on glycaemia. Studies on the molecular actions ofthese compounds indicate that thiazolidinediones and fibrates exerttheir action by activating distinct transcription factors of theperoxisome proliferator activated receptor (PPAR) family, resulting inincreased and decreased expression of specific enzymes andapolipoproteins respectively, both key-players in regulation of plasmatriglyceride content. Fibrates, on the one hand, are PPARα activators,acting primarily in the liver. Thiazolidinediones, on the other hand,are high affinity ligands for PPARγ acting primarily on adipose tissue.

Adipose tissue plays a central role in lipid homeostasis and themaintenance of energy balance in vertebrates. Adipocytes store energy inthe form of triglycerides during periods of nutritional affluence andrelease it in the form of free fatty acids at times of nutritionaldeprivation. The development of white adipose tissue is the result of acontinuous differentiation process throughout life. Much evidence pointsto the central role of PPARγ activation in initiating and regulatingthis cell differentiation. Several highly specialised proteins areinduced during adipocyte differentiation, most of them being involved inlipid storage and metabolism. The exact link from activation of PPARγ tochanges in glucose metabolism, most notably a decrease in insulinresistance in muscle, has not yet been clarified. A possible link is viafree fatty acids such that activation of PPARγ induces LipoproteinLipase (LPL), Fatty Acid Transport Protein (FATP) and Acyl-CoASynthetase (ACS) in adipose tissue but not in muscle tissue. This, inturn, reduces the concentration of free fatty acids in plasmadramatically, and due to substrate competition at the cellular level,skeletal muscle and other tissues with high metabolic rates eventuallyswitch from fatty acid oxidation to glucose oxidation with decreasedinsulin resistance as a consequence.

PPARα is involved in stimulating β-oxidation of fatty acids. In rodents,a PPARα-mediated change in the expression of genes involved in fattyacid metabolism lies at the basis of the phenomenon of peroxisomeproliferation, a pleiotropic cellular response, mainly limited to liverand kidney and which can lead to hepatocarcinogenesis in rodents. Thephenomenon of peroxisome proliferation is not seen in man. In additionto its role in peroxisome proliferation in rodents, PPARα is alsoinvolved in the control of HDL cholesterol levels in rodents and humans.This effect is, at least partially, based on a PPARα-mediatedtranscriptional regulation of the major HDL apolipoproteins, apo A-I andapo A-II. The hypotriglyceridemic action of fibrates and fatty acidsalso involves PPARα and can be summarised as follows: (I) an increasedlipolysis and clearance of remnant particles, due to changes inlipoprotein lipase and apo C-III levels, (II) a stimulation of cellularfatty acid uptake and their subsequent conversion to acyl-CoAderivatives by the induction of fatty acid binding protein and acyl-CoAsynthase, (III) an induction of fatty acid β-oxidation pathways, (IV) areduction in fatty acid and triglyceride synthesis, and finally (V) adecrease in VLDL production. Hence, both enhanced catabolism oftriglyceride-rich particles as well as reduced secretion of VLDLparticles constitutes mechanisms that contribute to the hypolipidemiceffect of fibrates.

A number of compounds have been reported to be useful in the treatmentof hyperglycemia, hyperlipidemia and hypercholesterolemia (U.S. Pat. No.5,306,726, PCT Publications nos. W091/19702, WO 95/03038, WO 96/04260,WO 94/13650, WO 94/01420, WO 97/36579, WO 97/25042, WO 95/17394, WO99/08501, WO 99/19313 and WO 99/16758).

SUMMARY OF THE INVENTION

Glucose lowering as a single approach does not overcome themacrovascular complications associated with Type 2 diabetes andmetabolic syndrome. Novel treatments of Type 2 diabetes and metabolicsyndrome must therefore aim at lowering both the overthypertriglyceridaemia associated with these syndromes as well asalleviation of hyperglycaemia.

The clinical activity of fibrates and thiazolidinediones indicates thatresearch for compounds displaying combined PPARα and PPARγ activationshould lead to the discovery of efficacious glucose and triglyceridelowering drugs that have great potential in the treatment of Type 2diabetes and the metabolic syndrome (i.e. impaired glucose tolerance,insulin resistance, hypertriglyceridaemia and/or obesity).

DETAILED DESCRIPTION OF THE INVENTION

Accordingly, the present invention relates to compounds of the generalformula (I):

-   wherein A is aryl or heteroaryl and wherein A is optionally    substituted with one or more substituents selected from hydroxy,    halogen, perhalomethyl, perhalomethoxy, acyl, cyano, amino,    C₁₋₆-alkylamino, C₁₋₆-dialkylamino, methylenedioxy, aralkenyl,    aralkynyl, heteroaryloxy, heteroaralkoxy, aralkyl, heteroaralkyl,    arylamino, or-   A is optionally substituted with C₁₋₆-alkyl, C₂₋₆-alkenyl or    C₂₋₆-alkynyl each of which is optionally substituted with one or    more substituents selected from C₁₋₆-alkoxycarbonyl or carboxy, or-   A is optionally substituted with C₁₋₆-alkoxy, C₁₋₆-alkylthio or    C₂₋₆-alkenyloxy each of which is optionally substituted with one or    more halogens, or-   A is optionally substituted with aryloxy, arylthio or aralkoxy each    of which is optionally substituted with one or more substituents    selected from C₁₋₆-alkoxy, nitro, carboxy or C₁₋₆-alkoxycarbonyl;    and-   X₁ and X₂ independently are-   hydrogen,-   aryl or heteroaryl each of which is optionally substituted with one    or more substituents selected from hydroxy, aryloxy, arylthio,    aralkoxy, heteroaryloxy, aralkoxy, C₁₋₆-alkoxy, C₁₋₆-alkylthio,    halogen, perhalomethyl, perhalomethoxy, acyl, aryl, heteroaryl,    aralkyl, heteroaralkyl, cyano, amino, C₁₋₆-alkylamino,    C₁₋₆-dialkylamino, arylamino or methylenedioxy, or aryl or    heteroaryl each of which is optionally substituted with one or more    substituents selected from C₁₋₆-alkyl, C₂₋₆-alkenyl or C₂₋₆-alkynyl    each of which is optionally substituted with hydroxy; or

A is selected from the ring systems consisting of

wherein the attachment point of A to the remaining part of the structureof formula (I) is as indicated on the chemical structures in Figure 1,and wherein A is optionally substituted with one or more substituentsselected from C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, hydroxy, aryloxy,arylthio, aralkoxy, C₁₋₆-alkoxy, C₁₋₆-alkylthio, heteroaryloxy,heteroaralkoxy, halogen, perhalomethyl, perhalomethoxy, acyl, aralkyl,heteroaralkyl, cyano, amino, C₁₋₆-alkylamino, C₁₋₆-dialkylamino,arylamino or methylenedioxy; and

-   wherein X₁ and X₂ are hydrogen; and-   R₅ is hydrogen or C₁₋₆-alkyl; and-   Y is hydrogen, or-   Y is C₁₋₁₂-alkyl, C₂₋₁₂-alkenyl, C₂₋₁₂-alkynyl, C₄₋₁₂-alkenynyl,    aralkyl or heteroaralkyl each of which is optionally substituted    with one or more substituents selected from halogen, C₁₋₆-alkyl,    perhalomethyl, hydroxy, aryl, heteroaryl, carboxy or amino; and-   Z is hydrogen, halogen, hydroxy, or-   Z is C₁₋₆-alkyl or C₁₋₆-alkoxy each of which is optionally    substituted with one or more substituents selected from halogen,    hydroxy, carboxy, amino, cyano or C₁₋₆-alkoxy; and-   Q is O, S or NR₆, wherein R₆ is hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl,    C₂₋₆-alkynyl, C₄₋₆-alkenynyl, aralkyl, heteroaralkyl and wherein R₆    is optionally substituted with one or more substituents selected    from halogen, hydroxy, C₁₋₆-alkoxy, amino or carboxy; and-   Ar is arylene, heteroarylene or a divalent heterocyclic group each    of which can be optionally substituted with one or more substituents    selected from C₁₋₆-alkyl, aryl or C₁₋₆-alkoxy each of which can be    optionally substituted with halogen, hydroxy, carboxy, cyano or    heterocyclyl; and-   R₁ is hydrogen, hydroxy or halogen; or R₁ forms a bond together with    R₂; and-   R₂ is hydrogen or C₁₋₆-alkyl; or R₂ forms a bond together with R₁;    and-   R₃ is hydrogen, or-   R₃ is C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₄₋₆-alkenynyl, aryl,    aralkyl, C₁₋₆-alkoxyC₁₋₆-alkyl, acyl, heterocyclyl, heteroaryl or    heteroaralkyl each of which is optionally substituted with one or    more substituents selected from halogen, perhalomethyl, hydroxy or    cyano; and-   R₄ is hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,    C₄₋₆-alkenynyl or aryl; and-   n is an integer ranging from 0 to 3; and-   m is an integer ranging from 0 to 1;    or a pharmaceutically acceptable salt thereof, or a pharmaceutically    acceptable solvate thereof, or any tautomeric forms, stereoisomers,    mixture of stereoisomers including a racemic mixture, or polymorphs.

In a preferred embodiment, the present invention is concerned withcompounds of formula (I)

-   wherein A is aryl or heteroaryl and wherein A is optionally    substituted with one or more substituents selected from hydroxy,    halogen, perhalomethyl, perhalomethoxy, acyl, cyano, amino,    C₁₋₆-alkylamino, C₁₋₆-dialkylamino, methylenedioxy, aralkenyl,    aralkynyl, heteroaryloxy, heteroaralkoxy, aralkyl, heteroaralkyl,    arylamino, or-   A is optionally substituted with C₁₋₆-alkyl, C₂₋₆-alkenyl or    C₂₋₆-alkynyl each of which is optionally substituted with one or    more substituents selected from C₁₋₆-alkoxycarbonyl or carboxy, or-   A is optionally substituted with C₁₋₆-alkoxy, C₁₋₆-alkylthio or    C₂₋₆-alkenyloxy each of which is optionally substituted with one or    more halogens, or-   A is optionally substituted with aryloxy, arylthio or aralkoxy each    of which is optionally substituted with one or more substituents    selected from C₁₋₆-alkoxy, nitro, carboxy or C₁₋₆-alkoxycarbonyl;    and-   X₁ and X₂ independently are-   hydrogen,-   aryl or heteroaryl each of which is optionally substituted with one    or more substituents selected from hydroxy, aryloxy, arylthio,    aralkoxy, heteroaryloxy, aralkoxy, C₁₋₆-alkoxy, C₁₋₆-alkylthio,    halogen, perhalomethyl, perhalomethoxy, acyl, aryl, heteroaryl,    aralkyl, heteroaralkyl, cyano, amino, C₁₋₆-alkylamino,    C₁₋₆-dialkylamino, arylamino or methylenedioxy, or aryl or    heteroaryl each of which is optionally substituted with one or more    substituents selected from C₁₋₆-alkyl, C₂₋₆-alkenyl or C₂₋₆-alkynyl    each of which is optionally substituted with hydroxy; or-   A is selected from the ring systems consisting of    wherein the attachment point of A to the remaining part of the    structure of formula (I) is as indicated on the chemical structures    in Figure 1, and wherein A is optionally substituted with one or    more substituents selected from C₁₋₆-alkyl, C₂₋₆-alkenyl,    C₂₋₆-alkynyl, hydroxy, aryloxy, arylthio, aralkoxy, C₁₋₆-alkoxy,    C₁₋₆-alkylthio, heteroaryloxy, heteroaralkoxy, halogen,    perhalomethyl, perhalomethoxy, acyl, aralkyl, heteroaralkyl, cyano,    amino, C₁₋₆-alkylamino, C₁₋₆-dialkylamino, arylamino or    methylenedioxy; and-   wherein X₁ and X₂ are hydrogen; and-   R₅ is hydrogen or C₁₋₆-alkyl; and-   Y is hydrogen, or-   Y is C₁₋₁₂-alkyl, C₂₋₁₂-alkenyl, C₂₋₁₂-alkynyl, C₄₋₁₂-alkenynyl,    aralkyl or heteroaralkyl each of which is optionally substituted    with one or more substituents selected from halogen, C₁₋₆-alkyl,    perhalomethyl, hydroxy, aryl, heteroaryl, carboxy or amino; and-   Z is hydrogen, halogen, hydroxy, or-   Z is C₁₋₆-alkyl or C₁₋₆-alkoxy each of which is optionally    substituted with one or more substituents selected from halogen,    hydroxy, carboxy, amino, cyano or C₁₋₆-alkoxy; and-   Q is O, S or NR₆, wherein R₆ is hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl,    C₂₋₆-alkynyl, C₄₋₆-alkenynyl, aralkyl, heteroaralkyl and wherein R₆    is optionally substituted with one or more substituents selected    from halogen, hydroxy, C₁₋₆-alkoxy, amino or carboxy; and-   Ar is arylene, heteroarylene or a divalent heterocyclic group each    of which can be optionally substituted with one or more substituents    selected from C₁₋₆-alkyl, aryl or C₁₋₆-alkoxy each of which can be    optionally substituted with halogen, hydroxy, carboxy, cyano or    heterocyclyl; and-   R₁ is hydrogen, hydroxy or halogen; or R₁ forms a bond together with    R₂; and-   R₂ is hydrogen or C₁₋₆-alkyl; or R₂ forms a bond together with R₁;    and-   R₃ is hydrogen, or-   R₃ is C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₄₋₆-alkenynyl, aryl,    aralkyl, C₁₋₆-alkoxyC₁₋₆-alkyl, acyl, heterocyclyl, heteroaryl or    heteroaralkyl each of which is optionally substituted with one or    more substituents selected from halogen, perhalomethyl, hydroxy or    cyano; and-   R₄ is hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,    C₄₋₆-alkenynyl or aryl; and-   n is an integer ranging from 1 to 3; and-   m is 1;-   or a pharmaceutically acceptable salt thereof, or a pharmaceutically    acceptable solvate thereof, or any tautomeric forms, stereoisomers,    mixture of stereoisomers including a racemic mixture, or polymorphs.

In another preferred embodiment, the present invention is concerned withcompounds of formula (I)

-   wherein A is aryl or heteroaryl and wherein A is optionally    substituted with one or more substituents selected from C₁₋₆-alkyl,    C₂₋₆-alkenyl, C₂₋₆-alkynyl, hydroxy, aryloxy, arylthio, aralkoxy,    C₁₋₆-alkoxy, C₁₋₆-alkylthio, heteroaryloxy, heteroaralkoxy, halogen,    perhalomethyl, perhalomethoxy, acyl, aralkyl, heteroaralkyl, cyano,    amino, C₁₋₆-alkylamino, C₁₋₆-dialkylamino, arylamino or    methylenedioxy, and-   X₁ and X₂ independently are hydrogen, aryl or heteroaryl optionally    substituted with one or more substituents selected from C₁₋₆-alkyl,    C₂₋₆-alkenyl, C₂₋₆-alkynyl, hydroxy, aryloxy, arylthio, aralkoxy,    heteroaryloxy, aralkoxy, C₁₋₆-alkoxy, C₁₋₆-alkylthio, halogen,    perhalomethyl, perhalomethoxy, acyl, aryl, heteroaryl, aralkyl,    heteroaralkyl, cyano, amino, C₁₋₆-alkylamino, C₁₋₆-dialkylamino,    arylamino or methylenedioxy;    or-   wherein A is selected from the ring systems consisting of-   wherein the attachment point of A to the remaining part of the    structure of formula (I) is as indicated on the chemical structures    in Figure 1, and-   wherein A is optionally substituted with one or more substituents    selected from C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, hydroxy,    aryloxy, arylthio, aralkoxy, C₁₋₆-alkoxy, C₁₋₆-alkylthio,    heteroaryloxy, heteroaralkoxy, halogen, perhalomethyl,    perhalomethoxy, acyl, aralkyl, heteroaralkyl, cyano, amino,    C₁₋₆-alkylamino, C₁₋₆-dialkylamino, arylamino or methylenedioxy, and    wherein X₁ and X₂ are hydrogen; and-   R₅ is hydrogen or C₁₋₆-alkyl; and-   Y is hydrogen, C₁₋₁₂-alkyl, C₂₋₁₂-alkenyl, C₂₋₁₂-alkynyl,    C₄₋₁₂-alkenynyl, aralkyl or heteroaralkyl optionally substituted    with one or more substituents selected from halogen, C₁₋₆-alkyl,    perhalomethyl, hydroxy, aryl, heteroaryl, carboxy or amino; and-   Z is hydrogen, halogen, hydroxy, C₁₋₆-alkyl or C₁₋₆-alkoxy    optionally substituted with one or more substituents selected from    halogen, hydroxy, carboxy, amino, cyano or C₁₋₆-alkoxy; and-   Q is O, S or NR₆, wherein R₆ is hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl,    C₂₋₆-alkynyl, C₄₋₆-alkenynyl, aralkyl, heteroaralkyl and wherein R₆    is optionally substituted with one or more substituents selected    from halogen, hydroxy, C₁₋₆-alkoxy, amino or carboxy; and-   Ar is arylene, heteroarylene or a divalent heterocyclic group each    of which can be optionally substituted with one or more substituents    selected from C₁₋₆-alkyl, aryl or C₁₋₆-alkoxy each of which can be    optionally substituted with halogen, hydroxy, carboxy, cyano or    heterocyclyl; and-   R₁ is hydrogen, hydroxy or halogen; or R₁ forms a bond together with    R₂; and-   R₂ is hydrogen or C₁₋₆-alkyl; or R₂ forms a bond together with R₁;    and-   R₃ is hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,    C₄₋₆-alkenynyl, aryl, aralkyl, C₁₋₆-alkoxyC₁₋₆-alkyl, acyl,    heterocyclyl, heteroaryl or heteroaralkyl groups optionally    substituted with one or more substituents selected from halogen,    perhalomethyl, hydroxy or cyano; and-   R₄ is hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,    C₄₋₆-alkenynyl or aryl; and-   n is an integer ranging from 0 to 3; and-   m is an integer ranging from 0 to 1.

In another preferred embodiment, the present invention is concerned withcompounds of formula (I)

-   wherein A is aryl or heteroaryl and wherein A is optionally    substituted with one or more substituents selected from C₁₋₆-alkyl,    C₂₋₆-alkenyl, C₂₋₆-alkynyl, hydroxy, aryloxy, arylthio, aralkoxy,    C₁₋₆-alkoxy, C₁₋₆-alkylthio, heteroaryloxy, heteroaralkoxy, halogen,    perhalomethyl, perhalomethoxy, acyl, aralkyl, heteroaralkyl, cyano,    amino, C₁₋₆-alkylamino, C₁₋₆-dialkylamino, arylamino or    methylenedioxy; or-   provided X₁ and X₂ is hydrogen, A is selected from the ring systems    consisting of-   wherein A is optionally substituted with one or more substituents    selected from C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, hydroxy,    aryloxy, arylthio, aralkoxy, C₁₋₆-alkoxy, C₁₋₆-alkylthio,    heteroaryloxy, heteroaralkoxy, halogen, perhalomethyl,    perhalomethoxy, acyl, aralkyl, heteroaralkyl, cyano, amino,    C₁₋₆-alkylamino, C₁₋₆-dialkylamino, arylamino or methylenedioxy; and-   R₅ is hydrogen or C₁₋₆-alkyl; and-   X₁ and X₂ independently are hydrogen, aryl or heteroaryl optionally    substituted with one or more substituents selected from C₁₋₆-alkyl,    C₂₋₆-alkenyl, C₂₋₆-alkynyl, hydroxy, aryloxy, arylthio, aralkoxy,    heteroaryloxy, aralkoxy, C₁₋₆-alkoxy, C₁₋₆-alkylthio, halogen,    perhalomethyl, perhalomethoxy, acyl, aryl, heteroaryl, aralkyl,    heteroaralkyl, cyano, amino, C₁₋₆-alkylamino, C₁₋₆-dialkylamino,    arylamino or methylenedioxy; and-   Y is hydrogen, C₁₋₁₂-alkyl, C₂₋₁₂-alkenyl, C₂₋₁₂-alkynyl,    C₄₋₁₂-alkenynyl, aralkyl or heteroaralkyl optionally substituted    with one or more substituents selected from halogen, C₁₋₆-alkyl,    perhalomethyl, hydroxy, aryl, heteroaryl, carboxy or amino; and-   Z is hydrogen, halogen, hydroxy, C₁₋₆-alkyl or C₁₋₆-alkoxy    optionally substituted with one or more substituents selected from    halogen, hydroxy, carboxy, amino, cyano or C₁₋₆-alkoxy; and-   Q is O, S or NR₆, wherein R₆ is hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl,    C₂₋₆-alkynyl, C₄₋₆-alkenynyl, aralkyl, heteroaralkyl and wherein R₆    is optionally substituted with one or more substituents selected    from halogen, hydroxy, C₁₋₆-alkoxy, amino or carboxy; and-   Ar is arylene, heteroarylene or a divalent heterocyclic group each    of which can be optionally substituted with one or more substituents    selected from C₁₋₆-alkyl, aryl or C₁₋₆-alkoxy each of which can be    optionally substituted with halogen, hydroxy, carboxy, cyano or    heterocyclyl; and-   R₁ is hydrogen, hydroxy or halogen; or R₁ forms a bond together with    R₂; and-   R₂ is hydrogen or C₁₋₆-alkyl; or R₂ forms a bond together with R₁;    and-   R₃ is hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,    C₄₋₆-alkenynyl, aryl, aralkyl, C₁₋₆-alkoxyC₁₋₆-alkyl, acyl,    heterocyclyl, heteroaryl or heteroaralkyl groups optionally    substituted with one or more substituents selected from halogen,    perhalomethyl, hydroxy or cyano; and-   R₄ is hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,    C₄₋₆-alkenynyl or aryl; and-   n is an integer ranging from 0 to 3; and-   m is an integer ranging from 0 to 1.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein A is aryl or heteroaryl optionallysubstituted with one or more substituents selected from from C₁₋₆-alkyl,C₂₋₆-alkenyl each of which is optionally substituted with one or moresubstituents selected from C₁₋₆-alkoxycarbonyl or carboxy, or

-   A is optionally substituted with aryloxy optionally substituted with    one or more C₁₋₆-alkoxy, or-   A is optionally substituted with aralkoxy optionally substituted    with one or more substituents selected from C₁₋₆-alkoxy, nitro,    carboxy or C₁₋₆-alkoxycarbonyl, or-   A is optionally substituted with C₁₋₆-alkoxy optionally substituted    with one or more halogens, or-   A is optionally substituted with aralkenyl, C₂₋₆-alkenyloxy,    aralkynyl, halogen, perhalomethyl, perhalomethoxy, acyl, aralkyl or    methylenedioxy.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein A is aryl, heteroaryl or

optionally substituted with one or more substituents selected fromaryloxy, arylthio, aralkoxy, C₁₋₆-alkoxy, C₁₋₆-alkylthio, halogen,perhalomethyl, aralkyl, heteroaralkyl, heteroaryloxy or heteroaralkoxy.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein A is aryl optionally substituted with oneor more substituents selected from aryloxy, arylthio, aralkoxy,C₁₋₆-alkoxy, C₁₋₆-alkylthio, halogen, perhalomethyl, aralkyl,heteroaralkyl, heteroaryloxy or heteroaralkoxy.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein A is aryl optionally substituted with oneor more substituents selected from from C₁₋₆-alkyl, C₂₋₆-alkenyl each ofwhich is optionally substituted with one or more substituents selectedfrom C₁₋₆-alkoxycarbonyl or carboxy, or

-   A is optionally substituted with aryloxy optionally substituted with    one or more C₁₋₆-alkoxy, or-   A is optionally substituted with aralkoxy optionally substituted    with one or more substituents selected from C₁₋₆-alkoxy, nitro,    carboxy or C₁₋₆-alkoxycarbonyl, or-   A is optionally substituted with C₁₋₆-alkoxy optionally substituted    with one or more halogens, or-   A is optionally substituted with aralkenyl, C₂₋₆-alkenyloxy,    aralkynyl, halogen, perhalomethyl, perhalomethoxy, acyl, aralkyl or    methylenedioxy.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein A is aryl optionally substituted with oneor more substituents selected from from C₁₋₆-alkyl, or

-   A is optionally substituted with aryloxy optionally substituted with    one or more C₁₋₆-alkoxy,-   A is optionally substituted with aralkoxy optionally substituted    with one or more substituents selected from C₁₋₆-alkoxy, or-   A is optionally substituted with C₁₋₆-alkoxy optionally substituted    with one or more halogens, or-   A is optionally substituted with aralkenyl, aralkynyl, halogen,    perhalomethyl, perhalomethoxy or aralkyl.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein A is heteroaryl optionally substitutedWith one or more substituents selected from aryloxy, arylthio, aralkoxy,C₁₋₆-alkoxy, C₁₋₆-alkylthio, halogen, perhalomethyl, aralkyl,heteroaralkyl, heteroaryloxy or heteroaralkoxy.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein A is heteroaryl.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein A is

optionally substituted with one or more substituents selected fromaryloxy, arylthio, aralkoxy, C₁₋₆-alkoxy, C₁₋₆-alkylthio, halogen,perhalomethyl, aralkyl, heteroaralkyl, heteroaryloxy or heteroaralkoxy.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein A is

optionally substituted with one or more substituents selected fromC₁₋₆-alkyl, and wherein R₅ is hydrogen or C₁₋₆-alkyl.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein X₁ and X₂ independently are hydrogen,aryl or heteroaryl optionally substituted with one or more substituentsselected from aryloxy, arylthio, aralkoxy, halogen, perhalomethyl, aryl,heteroaryl, aralkyl, heteroaralkyl, heteroaryloxy or heteroaralkoxy.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein X₁ and X₂ independently are

-   hydrogen,-   aryl or heteroaryl optionally substituted with one or more    substituents selected from halogen, acyl, aryl, or-   aryl or heteroaryl optionally substituted with one or more    substituents selected from C₁₋₆-alkyl, C₂₋₆-alkynyl each of which is    optionally substituted with hydroxy.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein X₁ and X₂ independently are

-   hydrogen, or-   aryl or heteroaryl optionally substituted with one or more    substituents selected from halogen.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein X₁ and X₂ independently are hydrogen oraryl optionally substituted with one or more substituents selected fromaryloxy, arylthio, aralkoxy, halogen, perhalomethyl, aryl, heteroaryl,aralkyl, heteroaralkyl, heteroaryloxy or heteroaralkoxy.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein X₁ and X₂ independently are

-   hydrogen,-   aryl optionally substituted with one or more substituents selected    from halogen, acyl, aryl, or-   aryl optionally substituted with one or more substituents selected    from C₁₋₆-alkyl, C₂₋₆-alkynyl each of which is optionally    substituted with hydroxy.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein X₁ and X₂ independently are

-   hydrogen, or-   phenyl optionally substituted with one or more substituents selected    from halogen.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein X₁ and X₂ independently are hydrogen orheteroaryl optionally substituted with one or more substituents selectedfrom aryloxy, arylthio, aralkoxy, halogen, perhalomethyl, aryl,heteroaryl, aralkyl, heteroaralkyl, heteroaryloxy or heteroaralkoxy.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein X₁ and X₂ independently are hydrogen orheteroaryl.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein X₁ and X₂ is hydrogen.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein Y is hydrogen or C₁₋₁₂-alkyl.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein Y is hydrogen or methyl.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein Z is hydrogen or C₁₋₆-alkoxy.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein Z is hydrogen or C₁₋₆-alkyl.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein Z is hydrogen.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein Q is O.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein Ar is arylene optionally substituted withone or more substituents selected from C₁₋₆-alkyl or C₁₋₆-alkoxy each ofwhich can be optionally substituted with carboxy.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein Ar is arylene.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein R₁ is hydrogen or R₁ forms a bondtogether with R₂.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein R₁ is hydrogen.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein R₂ is hydrogen or R₂ forms a bondtogether with R₁.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein R₂ is hydrogen.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein R₃ is C₁₋₆-alkyl or aralkyl.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein R₃ is C₁₋₆-alkyl.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein R₄ is hydrogen, C₁₋₃-alkyl.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein R₄ is hydrogen.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein n is 1.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein m is 1.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein alkyl is methyl, ethyl, n-propyl,iso-propyl, butyl, tert-butyl, pentyl, hexyl, cyclopropyl orcyclopentyl.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein alkenyl is vinyl or 1-propenyl.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein alkynyl is ethynyl, 1-propynyl and2-propynyl.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein alkoxy is methoxy, ethoxy, propoxy,butoxy, pentoxy, hexoxy, isopropoxy or cyclopentyloxy.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein alkylthio is methylthio, ethylthio,propylthio or cyclopentylthio.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein aryl is phenyl optionally substitutedwith halogen.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein arylene is phenylene optionallysubstituted with halogen.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein halogen is fluorine or chlorine.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein perhalomethyl is trifluoromethyl.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein acyl is acetyl.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein heteroaryl is furan, thiophene, pyrrole,imidazole, pyrazole, pyridine, quinoline, isoquinoline, quinazoline,quinoxaline, indole, benzimidazole or benzofuran. In another preferredembodiment, the present invention is concerned with compounds of formulaI wherein heteroaryl is furan, pyrrole, indole or benzofuran.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein heteroarylene is furan, thiophene,pyrrole, imidazole, pyrazole, triazole, pyridine, pyrazine, pyrimidineor pyridazine.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein aralkyl is benzyl or phenethyl.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein aryloxy is phenoxy.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein aralkoxy is benzyloxy.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein n is an integer ranging from 1 to 3 and mis 1.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein the substituents Z and Y are arranged ina trans-configuration.

In another preferred embodiment, the present invention is concerned withcompounds of formula I wherein the substituents Z and Y are arranged ina cis-configuration.

Preferred compounds of the invention are:

-   (E)-(S)-Ethyl    3-[4-(3-biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-ethoxy-propionate,-   (E)-(S)-3-[4-(3-Biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-ethoxy-propionic    acid,-   (E)-(S)-3-{4-[3-(4′-Bromo-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionic    acid ethyl ester,-   (E)-(S)-3-{4-[3-(4′-Bromo-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionic    acid,-   (E)-(S)-2-Ethoxy-3-{4-[3-(4-phenoxy-phenyl)-but-2-enyloxy]-phenyl}-propionic    acid ethyl ester,-   (E)-(S)-2-Ethoxy-3-{4-[3-(4-phenoxy-phenyl)-but-2-enyloxy]-phenyl}-propionic    acid,-   (E)-(S)-2-Ethoxy-3-(4-{3-[4-(4-methoxy-phenoxy)-phenyl]-but-2-enyloxy}-phenyl)-propionic    acid ethyl ester,-   (E)-(S)-2-Ethoxy-3-(4-{3-[4-(4-methoxy-phenoxy)-phenyl]-but-2-enyloxy}-phenyl)-propionic    acid,-   (E)-(S)-2-Ethoxy-3-{4-[3-(9H-fluoren-2-yl)-but-2-enyloxy]-phenyl}-propionic    acid ethyl ester,-   (E)-(S)-2-Ethoxy-3-{4-[3-(9H-fluoren-2-yl)-but-2-enyloxy]-phenyl}-propionic    acid,-   (E)-(S)-3-{4-[3-(3,4-Dimethoxy-phenyl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionic    acid ethyl ester,-   (E)-(S)-3-{4-[3-(3,4-Dimethoxy-phenyl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionic    acid,-   (E)-(S)-3-{4-[3-(3,5-Bis-trifluoromethyl-phenyl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionic    acid ethyl ester,-   (E)-(S)-3-{4-[3-(3,5-Bis-trifluoromethyl-phenyl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionic    acid,-   (E)-(S)-3-[4-(3-Biphenyl-4-yl-allyloxy)-phenyl]-2-ethoxy-propionic    acid ethyl ester,-   (E)-(S)-3-[4-(3-Biphenyl-4-yl-allyloxy)-phenyl]-2-ethoxy-propionic    acid,-   (E)-(S)-2-Ethoxy-3-[4-(3-naphthalen-2-yl-but-2-enyloxy)-phenyl]-propionic    acid ethyl ester,-   (E)-(S)-2-Ethoxy-3-[4-(3-naphthalen-2-yl-but-2-enyloxy)-phenyl]-propionic    acid,-   (E)-(S)-2-Ethoxy-3-[4-(3-pyridin-2-yl-but-2-enyloxy)-phenyl]-propionic    acid ethyl ester,-   (E)-(S)-2-Ethoxy-3-[4-(3-pyridin-2-yl-but-2-enyloxy)-phenyl]-propionic    acid,-   (E)-(S)-3-{4-[3-(3,5-Bis-benzyloxy-phenyl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionic    acid ethyl ester,-   (E)-(S)-3-{4-[3-(3,5-Bis-benzyloxy-phenyl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionic    acid,-   (E)-(S)-2-Ethoxy-3-[4-(3-naphthalen-2-yl-allyloxy)-phenyl]-propionic    acid ethyl ester,-   (E)-(S)-2-Ethoxy-3-[4-(3-naphthalen-2-yl-allyloxy)-phenyl]-propionic    acid,-   (E)-(S)-2-Ethoxy-3-{4-[3-(3-phenoxy-phenyl)-allyloxy]-phenyl}-propionic    acid ethyl ester,-   (E)-(S)-2-Ethoxy-3-{4-[3-(3-phenoxy-phenyl)-allyloxy]-phenyl}-propionic    acid,-   (S)-3-[4-(2-Benzofuran-3-yl-allyloxy)-phenyl]-2-ethoxy-propionic    acid ethyl ester,-   (S)-3-[4-(2-Benzofuran-3-yl-allyloxy)-phenyl]-2-ethoxy-propionic    acid;    or a salt thereof with a pharmaceutically acceptable acid or base,    or any optical isomer or mixture of optical isomers, including a    racemic mixture, or any tautomeric forms.

Also preferred compounds of the invention are:

-   (E)-(S)-3-{4-[3-(4-Benzyloxy-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionic    acid ethyl ester,-   (E)-(S)-3-{4-[3-(4-Benzyloxy-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionic    acid,-   (E)-(S)-3-[4-(3-Benzo[1,3]dioxol-5-yl-allyloxy)-phenyl]-2-ethoxy-propionic    acid ethyl ester,-   (E)-(S)-3-[4-(3-Benzo[1,3]dioxol-5-yl-allyloxy)-phenyl]-2-ethoxy-propionic    acid,-   (E)-(S)-3-{4-[3-(4-Allyloxy-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionic    acid ethyl ester,-   (E)-(S)-3-{4-[3-(4-Allyloxy-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionic    acid,-   (E)-(S)-3-[4-(3-Benzofuran-7-yl-allyloxy)-phenyl]-2-ethoxy-propionic    acid ethyl ester,-   (E)-(S)-3-[4-(3-Benzofuran-7-yl-allyloxy)-phenyl]-2-ethoxy-propionic    acid,-   (S)-3-[4-(3-Benzo[1,3]dioxol-4-yl-allyloxy)-phenyl]-2-ethoxy-propionic    acid ethyl ester,-   (S)-3-[4-(3-Benzo[1,3]dioxol-4-yl-allyloxy)-phenyl]-2-ethoxy-propionic    acid,-   (E)-(S)-2-Ethoxy-3-(4-[3-(9H-fluoren-2-yl)-allyloxy]-phenyl)-propionic    acid ethyl ester,-   (E)-(S)-2-Ethoxy-3-(4-[3-(9H-fluoren-2-yl)-allyloxy]-phenyl)-propionic    acid,-   (S)-2-Ethoxy-3-[4-(3-quinolin-2-yl-allyloxy)-phenyl]-propionic acid    ethyl ester,-   (S)-2-Ethoxy-3-[4-(3-quinolin-2-yl-allyloxy)-phenyl]-propionic acid,-   (E)-(S)-3-{4-[3-(3,5-Bis-benzyloxy-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionic    acid ethyl ester,-   (E)-(S)-3-{4-[3-(3,5-Bis-benzyloxy-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionic    acid,-   (E)-(S)-3-{4-[3-(3,5-Dimethoxy-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionic    acid ethyl ester,-   (E)-(S)-3-{4-[3-(3,5-Dimethoxy-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionic    acid,-   (E)-(S)-2-Ethoxy-3-[4-(3-phenanthren-9-yl-allyloxy)-phenyl]-propionic    acid ethyl ester,-   (E)-(S)-2-Ethoxy-3-{4-[3-(2-methoxy-naphthalen-1-yl)-allyloxy]-phenyl}-propionic    acid ethyl ester,-   (E)-(S)-2-Ethoxy-3-{4-[3-(2-methoxy-naphthalen-1-yl)-allyloxy]-phenyl}-propionic    acid,-   (E)-(S)-Ethyl    3-{4-[3-(4-Bromophenyl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate,-   (E)-(S)-3-{4-[3-(4-Bromophenyl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionic    acid,-   (E)-(S)-Ethyl    3-{4-[3-(4′-Chloro-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate,-   (E)-(S)-3-{4-[3-(4′-Chloro-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionic    acid,-   (E)-(S)-Ethyl    2-Ethoxy-3-{4-[3-(5′-isopropyl-2′-methoxy-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionate,-   (E)-(S)-2-Ethoxy-3-{4-[3-(5′-isopropyl-2′-methoxy-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionic    acid,-   (E)-(S)-Ethyl    2-Ethoxy-3-{4-[3-(5′-chloro-2′-methoxy-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionate,-   (E)-(S)-3-{4-[3-(5′-Chloro-2′-methoxy-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionic    acid,-   (E)-(S)-Ethyl    3-{4-[3-(2′,3′-Dichloro-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate,-   (E)-(S)-3-{4-[3-(2′,3′-Dichloro-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionic    acid,-   (E)-(S)-Ethyl    3-{4-[3-(2′,6′-Dimethoxy-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate,-   (E)-(S)-3-{4-[3-(2′,6′-Dimethoxy-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionic    acid,-   (E)-(S)-Ethyl    3-{4-[3-(4-Bromophenyl)-2-methyl-but-2-enyloxy]-phenyl}-2-ethoxy-propionate,-   (E)-(S)-3-{4-[3-(4-Bromophenyl)-2-methyl-but-2-enyloxy]-phenyl}-2-ethoxy-propionic    acid,-   (Z)-(S)-Ethyl    3-{4-[3-(4-Bromophenyl)-2-methyl-but-2-enyloxy]-phenyl}-2-ethoxy-propionate,-   (Z)-(S)-3-{4-[3-(4-Bromophenyl)-2-methyl-but-2-enyloxy]-phenyl}-2-ethoxy-propionic    acid,-   (E)-(S)-Ethyl    2-Ethoxy-3-[4-(3-[1,1′;3′,1″]terphenyl-4″-yl-but-2-enyloxy)-phenyl]-propionate,-   (E)-(S)-2-Ethoxy-3-[4-(3-[1,1′;3′,1″]terphenyl-4″-yl-but-2-enyloxy)-phenyl]-propionic    acid,-   (E)-(S)-Ethyl    2-Ethoxy-3-{4-[3-(3′-methyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionate,-   (E)-(S)-2-Ethoxy-3-{4-[3-(3′-methyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionic    acid,-   (E)-(S)-3-{4-[3-(3′-Acetyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate,-   (E)-(S)-2-Ethoxy-3-{4-[3-(5′-isopropyl-2′-methoxy-biphenyl-4-yl)-allyloxy]-phenyl}-propionic    acid ethyl ester,-   (E)-(S)-2-    Ethoxy-3-{4-[3-(5′-isopropyl-2′-methoxy-biphenyl-4-yl)-allyloxy]-phenyl}-propionic    acid,-   (E)-(S)-3-{4-[3-(3,5-Distyryl-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionic    acid ethyl ester,-   (E)-(S)-3-{4-[3-(3,5-Distyryl-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionic    acid;    or a salt thereof with a pharmaceutically acceptable acid or base,    or any optical isomer or mixture of optical isomers, including a    racemic mixture, or any tautomeric forms.

Also preferred compounds of the invention are:

-   (E)-(S)-3-{4-[3-(3,5-Diisopropoxy-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionic    acid ethyl ester,-   (E)-(S)-3-{4-[3-(3,5-Diisopropoxy-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionic    acid,-   (S)-3-{4-[3-(3-Bromo-5-styryl-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionic    acid ethyl ester,-   (S)-3-{4-[3-(3-Bromo-5-styryl-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionic    acid,-   (E)-(S)-2-Ethoxy-3-[4-(3-phenyl-allyloxy)-phenyl]-propionic acid    ethyl ester,-   (E)-(S)-2-Ethoxy-3-[4-(3-phenyl-allyloxy)-phenyl]-propionic acid,-   (E)-(S)-3-{4-[3-(2′,3′-Dichloro-biphenyl-4-yl)-allyloxy]-phenyl}-2-ethoxy-propionic    acid ethyl ester,-   (E)-(S)-3-{4-[3-(2′,3′-Dichloro-biphenyl-4-yl)-allyloxy]-phenyl}-2-ethoxy-propionic    acid,-   (E)-(S)-3-{4-[3-(3,5-Bis-phenylethynyl-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionic    acid ethyl ester,-   (E)-(S)-3-{4-[3-(3,5-Bis-phenylethynyl-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionic    acid,-   (E)-(S)-3-{4-[3-(3,5-Diphenethyl-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionic    acid ethyl ester,-   (E)-(S)-3-{4-[3-(3,5-Diphenethyl-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionic    acid,-   3-{4-[3-(3,5-Bis-cyclopentyloxy-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionic    acid ethyl ester,-   (E)-(S)-3-{4-[3-(3,5-Bis-cyclopentyloxy-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionic    acid,-   (E)-(S)-3-(4-{3-[3,5-Bis-(2,2,2-trifluoro-ethoxy)-phenyl]-allyloxy}-phenyl)-2-ethoxy-propionic    acid ethyl ester,-   (E)-(S)-3-(4-{3-[3,5-Bis-(2,2,2-trifluoro-ethoxy)-phenyl]-allyloxy}-phenyl)-2-ethoxy-propionic    acid,-   (E)-(S)-Ethyl    2-Ethoxy-3-{4-[3-(4-furan-2-yl-phenyl)-but-2-enyloxy]-phenyl}-propionate,-   (E)-(S)-Ethyl    2-Ethoxy-3-{4-[3-(2′-methyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionate,-   (E)-(S)-2-Ethoxy-3-{4-[3-(2′-methyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionic    acid,-   (E)-(S)-Ethyl    3-{4-[3-(2′,5′-Dimethoxy-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate,-   (E)-(S)-3-{4-[3-(2′,5′-Dimethoxy-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionic    acid,-   (E)-(S)-Ethyl    3-{4-[3-(4-Bromophenyl)-2-ethyl-but-2-enyloxy]-phenyl}-2-ethoxy-propionate,-   (E)-(S)-3-{4-[3-(4-Bromophenyl)-2-ethyl-but-2-enyloxy]-phenyl}-2-ethoxy-propionic    acid,-   (Z)-(S)-Ethyl    3-{4-[3-(4-Bromophenyl)-2-ethyl-but-2-enyloxy]-phenyl}-2-ethoxy-propionate,-   (Z)-(S)-3-{4-[3-(4-Bromophenyl)-2-ethyl-but-2-enyloxy]-phenyl}-2-ethoxy-propionic    acid,-   (E)-(S)-Ethyl    3-{4-[3-(4′-tert-Butyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate,-   (E)-(S)-Ethyl    3-{4-[3-(3′,5′-Bis-trifluoromethyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate,-   (E)-(S)-3-{4-[3-(3′,5′-Bis-trifluoromethyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionic    acid,-   (E)-(S)-Ethyl    2-Ethoxy-3-{4-[3-(4′-isopropyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionate,-   (E)-(S)-2-Ethoxy-3-{4-[3-(4′-isopropyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionic    acid,-   (E)-(S)-3-{4-[3-(3,5-Dimethoxy-phenyl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionic    acid ethyl ester,-   (E)-(S)-3-{4-[3-(3′-Acetyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionic    acid,-   (E)-(S)-Ethyl    3-{4-[3-(4′-Acetyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate,-   (E)-(S)-3-{4-[3-(4′-Acetyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionic    acid,-   (E)-(S)-Ethyl    2-Ethoxy-3-[4-(3-[1,1′;3′,1″]terphenyl-5′-yl-allyloxy)-phenyl]-propionate,-   (E)-(S)-2-Ethoxy-3-[4-(3-[1,1′;3′,1″]terphenyl-5′-yl-allyloxy)-phenyl]-propionic    acid,-   (E,E)-(S)-Ethyl    3-(4′-{3-[4-(2-Ethoxy-2-ethoxycarbonyl-ethyl)-phenoxy]-1-methyl-propenyl}-biphenyl-3-yl)-but-2-enoate,-   (E,E)-(S)-3-(4′-{3-[4-(2-Carboxy-2-ethoxy-ethyl)-phenoxy]-1-methyl-propenyl}-biphenyl-3-yl)-but-2-enoic    acid,-   (E)-(S)-Ethyl    2-Ethoxy-3-{4-[3-(3′-methoxy-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionate,-   (E)-(S)-2-Ethoxy-3-{4-[3-(3′-methoxy-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionic    acid,-   (E)-(S,S/R)-Ethyl    2-Ethoxy-3-(4-{3-[3′-(1-hydroxy-ethyl)-biphenyl-4-yl]-but-2-enyloxy}-phenyl)-propionate,-   (E)-(S,S/R)-2-Ethoxy-3-(4-{3-[3′-(1-hydroxy-ethyl)-biphenyl-4-yl]-but-2-enyloxy}-phenyl)-propionic    acid,-   (E)-(S)-Ethyl    3-{4-[3-(3,5-Dibromophenyl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate,-   (E)-(S)-3-{4-[3-(3,5-Dibromophenyl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionic    acid,-   (E)-(S)-Ethyl    3-{4-[3-(3,5-Dibromophenyl)-allyloxy]-phenyl}-2-ethoxy-propionate,-   (E)-(S)-3-{4-[3-(3,5-Dibromophenyl)-allyloxy]-phenyl}-2-ethoxy-propionic    acid,-   (E)-(S)-Ethyl    3-{4-[3-(4,4″-Di-tert-butyl-[1,1′;3′,1″]terphenyl-5′-yl)-allyloxy]-phenyl}-2-ethoxy-propionate,-   (E)-(S)-3-{4-[3-(4,4″-Di-tert-butyl-[1,1′;3′,1″]terphenyl-5′-yl)-allyloxy]-phenyl}-2-ethoxy-propionic    acid,-   (E)-(S)-Ethyl    3-{4-[3-(3′,5′-Dibromo-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate,-   (E)-(S)-3-{4-[3-(3′,5′-Dibromo-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionic    acid,-   (E)-(S)-Ethyl    3-{4-[3-(3′,5′-Dichloro-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate,-   (E)-(S)-3-{4-[3-(3′,5′-Dichloro-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionic    acid,-   (E)-(S)-Ethyl    3-{4-[3-(3′,5′-Dichloro-biphenyl-4-yl)-allyloxy]-phenyl}-2-ethoxy-propionate,-   (E)-(S)-3-{4-[3-(3′,5′-Dichloro-biphenyl-4-yl)-allyloxy]-phenyl}-2-ethoxy-propionic    acid,-   (E)-(S)-Ethyl    3-{4-[3-(3′,5′-di-tert-butyl-biphenyl-4-yl)-allyloxy]-phenyl}-2-ethoxy-propionate,-   (E)-(S)-3-{4-[3-(3′,5′-Di-tert-butyl-biphenyl-4-yl)-allyloxy]-phenyl}-2-ethoxy-propionic    acid,-   (E)-(S)-Ethyl    3-{4-[3-(3′,5′-Di-tert-butyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate,-   (E)-(S)-3-{4-[3-(3′,5′-Di-tert-butyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionic    acid,-   (E)-(S/R)-Ethyl    3-[4-(3-Biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-isopropoxy-propionate,-   (E)-(S/R)-3-[4-(3-Biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-isopropoxy-propionic    acid,-   (E)-(S/R)-Ethyl    3-[4-(3-Biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-butoxy-propionate,-   (E)-(S/R)-3-[4-(3-Biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-butoxy-propionic    acid,-   (E)-(S/R)-Ethyl    3-[4-(3-Biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-hexyloxy-propionate,-   (E)-(S/R)-3-[4-(3-Biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-hexyloxy-propionic    acid,-   (E)-(S/R)-Ethyl    3-[4-(3-Biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-(3-phenyl-propoxy)-propionate,-   (E)-(S/R)-3-[4-(3-Biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-(3-phenyl-propoxy)-propionic    acid,-   (E)-(S/R)-Ethyl    3-[4-(3-Biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-(4-phenyl-butoxy)-propionate,-   (E)-(S/R)-3-[4-(3-Biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-(4-phenyl-butoxy)-propionic    acid,-   (E)-(S/R)-Propyl    3-[4-(3-Biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-propoxy-propionate,-   (E)-(S/R)-3-[4-(3-Biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-propoxy-propionic    acid,-   (E)-(S)-3-{4-[3-(3,5-Diethoxyoxy-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionic    acid ethyl ester,-   (E)-(S)-3-{4-[3-(3,5-Diethoxyoxy-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionic    acid,-   (E)-(S)-3-{4-[3-(3,5-Bis-trifluoromethyl-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionic    acid ethyl ester,-   (E)-(S)-3-{4-[3-(3,5-Bis-trifluoromethyl-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionic    acid,-   (E)-(R,S)-3-[4-(3-Biphenyl-4-yl-allyloxy)-phenyl]-2-ethoxy-propionic    acid ethyl ester,-   (E)-(R,S)-3-[4-(3-Biphenyl-4-yl-allyloxy)-phenyl]-2-ethoxy-propionic    acid,-   (E)-(S)-4-(3-{3-[4-(2-Ethoxy-2-ethoxycarbonyl-ethyl)-phenoxy]-propenyl}-phenoxymethyl)-benzoic    acid methyl ester,-   (E)-(S)-4-(3-{3-[4-(2-Carboxy-2-ethoxy-ethyl)-phenoxy]-propenyl}-phenoxymethyl)-benzoic    acid;    or a salt thereof with a pharmaceutically acceptable acid or base,    or any optical isomer or mixture of optical isomers, including a    racemic mixture, or any tautomeric forms.

Also preferred compounds of the invention are:

-   (E)-(S)-Ethyl    2-Ethoxy-3-{4-[3-(4′-fluoro-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionate,-   (E)-(S)-2-Ethoxy-3-{4-[3-(4′-fluoro-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionic    acid,-   (E)-(S)-Ethyl    2-Ethoxy-3-{4-[3-(4-Iodophenyl)-but-2-enyloxy]-phenyl}-propionate;    or a salt thereof with a pharmaceutically acceptable acid or base,    or any optical isomer or mixture of optical isomers, including a    racemic mixture, or any tautomeric forms.

In the above structural formulas and throughout the presentspecification, the following terms have the indicated meaning:

The term “C₁₋₁₂-alkyl” as used herein, alone or in combination isintended to include those alkyl groups of the designated length ineither a linear or branched or cyclic configuration represents e.g.cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl andcyclooctyl and the like. Typical C₁₋₁₂-alkyl groups include, but are notlimited to, methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl,sec-butyl, tert-butyl, pentyl, iso-pentyl, hexyl, iso-hexyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl andcyclooctyl and the like, especially preferred is methyl, ethyl,n-propyl, iso-propyl, butyl, tert-butyl, pentyl, hexyl, cyclopropyl andcyclopentyl.

The term “C₂₋₁₂-alkenyl” as used herein, represents an olefinicallyunsaturated branched or straight group having from 2 to the specifiednumber of carbon atoms and at least one double bond. Examples of suchgroups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl,allyl, iso-propenyl, 1,3-butadienyl, 1-butenyl, hexenyl, pentenyl andthe like, especially preferred is vinyl and 1-propenyl.

The term “C₂₋₁₂-alkynyl”, as used herein, represent an unsaturatedbranched or straight group having from 2 to the specified number ofcarbon atoms and at least one triple bond. Examples of such groupsinclude, but are not limited to ethynyl, 1-propynyl, 2-propynyl,1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl and the like, especiallypreferred is ethynyl, 1-propynyl and 2-propynyl.

The term “C₄₋₁₂-alkenynyl” as used herein, represent an unsaturatedbranched or straight hydrocarbon group having from 4 to the specifiednumber of carbon atoms and both at least one double bond and at leastone triple bond. Examples of such groups include, but are not limitedto, 1-penten-4-yne, 3-penten-1-yne, 1,3-hexadiene-5-yne and the like.

The term “C₁₋₆-alkoxy” as used herein, alone or in combination isintended to include those C₁₋₆-alkyl groups of the designated length ineither a linear or branched or cyclic configuration linked thorugh anether oxygen having its free valence bond from the ether oxygen.Examples of linear alkoxy groups are methoxy, ethoxy, propoxy, butoxy,pentoxy, hexoxy and the like, especially preferred is methoxy, ethoxy,propoxy, butoxy, pentoxy, hexoxy. Examples of branched alkoxy areisopropoxy, sec-butoxy, tert-butoxy, isopentoxy, isohexoxy and the like,especially preferred is isopropoxy. Examples of cyclic alkoxy arecyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and thelike, especially preferred is cyclopentyloxy.

The term “C₁₋₆-alkylthio” as used herein, alone or in combination,refers to a straight or branched or cyclic monovalent substituentcomprising a C₁₋₆-alkyl group linked through a divalent sulfur atomhaving its free valence bond from the sulfur atom and having 1 to 6carbon atoms e.g. methylthio, ethylthio, propylthio, butylthio,pentylthio and the like, especially preferred is methylthio, ethylthioand propylthio. Examples of cyclic alkylthio are cyclopropylthio,cyclobutylthio, cyclopentylthio, cyclohexylthio and the like, especiallypreferred is cyclopentylthio.

The term “C₁₋₆-alkylamino” as used herein, alone or in combination,refers to a straight or branched or cyclic monovalent substituentcomprising a C₁₋₆-alkyl group linked through amino having a free valencebond from the nitrogen atom e.g. methylamino, ethylamino, propylamino,butylamino, pentylamino and the like. Examples of cyclic alkylamino arecyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino andthe like.

The term “arylamino” as used herein, alone or in combination, refers toan aryl as defined herein linked through amino having a free valencebond from the nitrogen atom e.g. phenylamino, naphthylamino and thelike.

The term “C₁₋₆-alkoxyC₁₋₆-alkyl” as used herein, alone or incombination, refers to a C₁₋₆-alkyl as defined herein whereto isattached a C₁₋₆-alkoxy as defined herein, e.g. methoxymethyl,ethoxymethyl, methoxyethyl, ethoxyethyl and the like.

The term “aryl” is intended to include a bicyclic aromatic ring, such ascarbocyclic aromatic rings selected from the group consisting of phenyland naphthyl, (1-naphthyl or 2-naphthyl), optionally substituted withhalogen, amino, hydroxy, C₁₋₆-alkyl, C₁₋₆-alkoxy, carboxy orC₁₋₆-alkylester and the like, especially preferred is halogen.

The term “arylene” is intended to include divalent aromatic rings, suchas carbocyclic aromatic rings selected from the group consisting ofphenylene, naphthylene and the like optionally substituted with halogen,amino, hydroxy, C₁₋₆-alkyl, C₁₋₆-alkoxy, carboxy or C₁₋₆-alkylester andthe like.

The term “halogen” means fluorine, chlorine, bromine or iodine,especially preferred is fluorine and chlorine.

The term “perhalomethyl” means trifluoromethyl, trichloromethyl,tribromomethyl or triiodomethyl, especially preferred istrifluoromethyl.

The term “C₁₋₆-dialkylamino” as used herein refers to an amino groupwherein the two hydrogen atoms independently are substituted with astraight or branched, saturated hydrocarbon chain having the indicatednumber of carbon atoms; such as dimethylamino, N-ethyl-N-methylamino,diethylamino, dipropylamino, N-(n-butyl)-N-methylamino,di(n-pentyl)amino and the like.

The term “acyl” as used herein refers to a monovalent substituentcomprising a C₁₋₆-alkyl group linked through a carbonyl group; such ase.g. acetyl, propionyl, butyryl, isobutyryl, pivaloyl, valeryl and thelike, especially preferred is acetyl.

The term “heteroaryl” as used herein, alone or in combination, refers toa monovalent substituent comprising a 5-6 membered monocyclic aromaticsystem or a 9-10 membered bicyclic aromatic system containing one ormore heteroatoms selected from nitrogen, oxygen and sulfur, e.g. furan,thiophene, pyrrole, imidazole, pyrazole, triazole, pyridine, pyrazine,pyrimidine, pyridazine, isothiazole, isoxazole, oxazole, oxadiazole,thiadiazole, quinoline, isoquinoline, quinazoline, quinoxaline, indole,benzimidazole, benzofuran, pteridine and purine and the like, preferredis furan, thiophene, pyrrole, imidazole, pyrazole, pyridine, quinoline,isoquinoline, quinazoline, quinoxaline, indole, benzimidazole,benzofuran, especially preferred is furan, pyrrole, indole andbenzofuran.

The term “heteroarylene” as used herein, alone or in combination, refersto a divalent group comprising a 5-6 membered monocyclic aromatic systemor a 9-10 membered bicyclic aromatic system containing one or moreheteroatoms selected from nitrogen, oxygen and sulfur, e.g. furan,thiophene, pyrrole, imidazole, pyrazole, triazole, pyridine, pyrazine,pyrimidine, pyridazine, isothiazole, isoxazole, oxazole, oxadiazole,thiadiazole, quinoline, isoquinoline, quinazoline, quinoxaline, indole,benzimidazole, benzofuran, pteridine and purine and the like, especiallypreferred is furan, thiophene, pyrrole, imidazole, pyrazole, triazole,pyridine, pyrazine, pyrimidine, pyridazine.

The term “heteroaryloxy” as used herein, alone or in combination, refersto a heteroaryl as defined herein linked to an oxygen atom having itsfree valence bond from the oxygen atom e.g. pyrrole, imidazole,pyrazole, triazole, pyridine, pyrazine, pyrimidine, pyridazine,isothiazole, isoxazole, oxazole, oxadiazole, thiadiazole, quinoline,isoquinoline, quinazoline, quinoxaline, indole, benzimidazole,benzofuran, pteridine and purine linked to oxygen, and the like.

The term “aralkyl” as used herein refers to a straight or branchedsaturated carbon chain containing from 1 to 6 carbons substituted withan aromatic carbohydride; such as benzyl, phenethyl, 3-phenylpropyl,1-naphthylmethyl, 2-(1-naphthyl)ethyl and the like, especially preferredis benzyl and phenethyl.

The term “aryloxy” as used herein refers to phenoxy, 1-naphthyloxy,2-naphthyloxy and the like, especially preferred is phenoxy.

The term “aralkoxy” as used herein refers to a C₁₋₆-alkoxy groupsubstituted with an aromatic carbohydride, such as benzyloxy,phenethoxy, 3-phenylpropoxy, 1-naphthylmethoxy, 2-(1-naphthyl)ethoxy andthe like, especially preferred is benzyloxy.

The term “heteroaralkyl” as used herein refers to a straight or branchedsaturated carbon chain containing from 1 to 6 carbons substituted with aheteroaryl group; such as (2-furyl)methyl, (3-furyl)methyl,(2-thienyl)methyl, (3-thienyl)methyl, (2-pyridyl)methyl,1-methyl-1-(2-pyrimidyl)ethyl and the like.

The term “heteroaralkoxy” as used herein refers to a heteroaralkyl asdefined herein linked to an oxygen atom having its free valence bondfrom the oxygen atom, e.g. (2-furyl)methyl, (3-furyl)methyl,(2-thienyl)methyl, (3-thienyl)methyl, (2-pyridyl)methyl,1-methyl-1-(2-pyrimidyl)ethyl linked to oxygen, and the like.

The term “arylthio” as used herein, alone or in combination, refers toan aryl group linked through a divalent sulfur atom having its freevalence bond from the sulfur atom, the aryl group optionally being mono-or polysubstituted with C₁₋₆-alkyl, halogen, hydroxy or C₁₋₆-alkoxy;e.g. phenylthio, (4-methylphenyl)-thio, (2-chlorophenyl)thio and thelike.

As used herein, the phrase “heterocyclyl” means a monovalent saturatedor unsaturated non aromatic group being monocyclic and containing one ormore, such as from one to four carbon atom(s), and from one to four N, Oor S atom(s) or a combination thereof. The phrase “heterocyclyl”includes, but is not limited to, 5-membered heterocycles having onehetero atom (e.g. pyrrolidine, pyrroline and the like); 5-memberedheterocycles having two heteroatoms in 1,2 or 1,3 positions (e.g.pyrazoline, pyrazolidine, 1,2-oxathiolane, imidazolidine, imidazoline,4-oxazolone and the like); 5-membered heterocycles having threeheteroatoms (e.g. tetrahydrofurazan and the like); 5-memberedheterocycles having four heteroatoms; 6-membered heterocycles with oneheteroatom (e.g. piperidine and the like); 6-membered heterocycles withtwo heteroatoms (e.g. piperazine, morpholine and the like); 6-memberedheterocycles with three heteroatoms; and 6-membered heterocycles withfour heteroatoms, and the like.

As used herein, the phrase “a divalent heterocyclic group” means adivalent saturated or unsaturated system being monocyclic and containingone or more, such as from one to four carbon atom(s), and one to four N,O or S atom(s) or a combination thereof. The phrase a divalentheterocyclic group includes, but is not limited to, 5-memberedheterocycles having one hetero atom (e.g. pyrrolidine, pyrroline and thelike); 5-membered heterocycles having two heteroatoms in 1,2 or 1,3positions (e.g. pyrazoline, pyrazolidine, 1,2-oxathiolane,imidazolidine, imidazoline, 4-oxazolone and the like); 5-memberedheterocycles having three heteroatoms (e.g. tetrahydrofurazan and thelike); 5-membered heterocycles having four heteroatoms; 6-memberedheterocycles with one heteroatom (e.g. piperidine and the like);6-membered heterocycles with two heteroatoms (e.g. piperazine,morpholine and the like); 6-membered heterocycles with threeheteroatoms; and 6-membered heterocycles with four heteroatoms, and thelike.

As used herein the term “treatment” includes treatment, prevention andmanagement of such condition.

Certain of the above defined terms may occur more than once in the aboveformula (I), and upon such occurrence each term shall be definedindependently of the other.

The present invention also encompasses pharmaceutically acceptable saltsof the present compounds. Such salts include pharmaceutically acceptableacid addition salts, pharmaceutically acceptable base addition salts,pharmaceutically acceptable metal salts, ammonium and alkylated ammoniumsalts. Acid addition salts include salts of inorganic acids as well asorganic acids. Representative examples of suitable inorganic acidsinclude hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric,nitric acids and the like. Representative examples of suitable organicacids include formic, acetic, trichloroacetic, trifluoroacetic,propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic,malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic,methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic,bismethylene salicylic, ethanedisulfonic, gluconic, citraconic,aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic,benzenesulfonic, p-toluenesulfonic acids, sulphates, nitrates,phosphates, perchlorates, borates, acetates, benzoates,hydroxynaphthoates, glycerophosphates, ketoglutarates and the like.Further examples of pharmaceutically acceptable inorganic or organicacid addition salts include the pharmaceutically acceptable salts listedin J. Pharm. Sci. 1977, 66, 2, which is incorporated herein byreference. Examples of metal salts include lithium, sodium, potassium,magnesium salts and the like. Examples of ammonium and alkylatedammonium salts include ammonium, methylammonium, dimethylammonium,trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium,butylammonium, tetramethylammonium salts and the like. Examples oforganic bases include lysine, arginine, guanidine, diethanolamine,choline and the like.

The pharmaceutically acceptable salts are prepared by reacting thecompound of formula I with 1 to 4 equivalents of a base such as sodiumhydroxide, sodium methoxide, sodium hydride, potassium t-butoxide,calcium hydroxide, magnesium hydroxide and the like, in solvents likeether, THF, methanol, t-butanol, dioxane, isopropanol, ethanol etc.Mixture of solvents may be used. Organic bases like lysine, arginine,diethanolamine, choline, guandine and their derivatives etc. may also beused. Alternatively, acid addition salts wherever applicable areprepared by treatment with acids such as hydrochloric acid, hydrobromicacid, nitric acid, □immer□e□ acid, phosphoric acid, p-toluenesulphonicacid, methanesulfonic acid, acetic acid, citric acid, maleic acidsalicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid,succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid and thelike in solvents like ethyl acetate, ether, alcohols, acetone, THF,dioxane etc. Mixture of solvents may also be used.

The stereoisomers of the compounds forming part of this invention may beprepared by using reactants in their single enantiomeric form in theprocess wherever possible or by conducting the reaction in the presenceof reagents or catalysts in their single enantiomer form or by resolvingthe mixture of stereoisomers by conventional methods. Some of thepreferred methods include use of microbial resolution, enzymaticresolution, resolving the diastereomeric salts formed with chiral acidssuch as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid,and the like wherever applicable or chiral bases such as brucine, (R)-or (S)-phenylethylamine, cinchona alkaloids and their derivatives andthe like. Commonly used methods are compiled by Jaques et al in“Enantiomers, Racemates and Resolution” (Wiley Interscience, 1981). Morespecifically the compound of formula I may be converted to a 1:1 mixtureof diastereomeric amides by treating with chiral amines, aminoacids,aminoalcohols derived from aminoacids; conventional reaction conditionsmay be employed to convert acid into an amide; the dia-stereomers may beseparated either by fractional crystallization or chromatography and thestereoisomers of compound of formula I may be prepared by hydrolysingthe pure diastereomeric amide.

Various polymorphs of compound of general formula I forming part of thisinvention may be prepared by crystallization of compound of formula Iunder different conditions. For example, using different solventscommonly used or their mixtures for recrystallization; crystallizationsat different temperatures; various modes of cooling, ranging from veryfast to very slow cooling during crystallizations. Polymorphs may alsobe obtained by heating or melting the compound followed by gradual orfast cooling. The presence of polymorphs may be determined by solidprobe nmr spectroscopy, ir spectroscopy, differential scanningcalorimetry, powder X-ray diffraction or such other techniques.

The invention also encompasses prodrugs of the present compounds, whichon administration undergo chemical conversion by metabolic processesbefore becoming active pharmacological substances. In general, suchprodrugs will be functional derivatives of the present compounds, whichare readily convertible in vivo into the required compound of theformula (I). Conventional procedures for the selection and preparationof suitable prodrug derivatives are described, for example, in “Designof Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

The invention also encompasses active metabolites of the presentcompounds.

Furthermore, the present compounds of formula I can be utilised in thetreatment and/or prevention of conditions mediated by nuclear receptors,in particular the Peroxisome Proliferator-Activated Receptors (PPAR).

In a further aspect, the present invention relates to a method oftreating and/or preventing Type I or Type II diabetes.

In a still further aspect, the present invention relates to the use ofone or more compounds of the general formula I or pharmaceuticallyacceptable salts thereof for the preparation of a medicament for thetreatment and/or prevention of Type I or Type II diabetes.

In a still further aspect, the present compounds are useful for thetreatment and/or prevention of IGT.

In a still further aspect, the present compounds are useful for thetreatment and/or prevention of Type 2 diabetes.

In a still further aspect, the present compounds are useful for thedelaying or prevention of the progression from IGT to Type 2 diabetes.

In a still further aspect, the present compounds are useful for thedelaying or prevention of the progression from non-insulin requiringType 2 diabetes to insulin requiring Type 2 diabetes.

In another aspect, the present compounds reduce blood glucose andtriglyceride levels and are accordingly useful for the treatment and/orprevention of ailments and disorders such as diabetes and/or obesity.

In still another aspect, the present compounds are useful for thetreatment and/or prophylaxis of insulin resistance (Type 2 diabetes),impaired glucose tolerance, dyslipidemia, disorders related to SyndromeX such as hypertension, obesity, insulin resistance, hyperglycaemia,atherosclerosis, hyperlipidemia, coronary artery disease, myocardialischemia and other cardiovascular disorders.

In still another aspect, the present compounds are effective indecreasing apoptosis in mammalian cells such as beta cells of Islets ofLangerhans.

In still another aspect, the present compounds are useful for thetreatment of certain renal diseases including glomerulonephritis,glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis.

In still another aspect, the present compounds may also be useful forimproving cognitive functions in dementia, treating diabeticcomplications, psoriasis, polycystic ovarian syndrome (PCOS) andprevention and treatment of bone loss, e.g. osteoporosis.

The invention also relates to pharmaceutical compositions comprising, asan active ingredient, at least one compound of the formula I or anyoptical or geometric isomer or tautomeric form thereof includingmixtures of these or a pharmaceutically acceptable salt thereof togetherwith one or more pharmaceutically acceptable carriers or diluents.

Furthermore, the invention relates to the use of compounds of thegeneral formula I or their tautomeric forms, their stereoisomers, theirpolymorphs, their pharmaceutically acceptable salts or pharmaceuticallyacceptable solvates thereof for the preparation of a pharmaceuticalcomposition for the treatment and/or prevention of conditions mediatedby nuclear receptors, in particular the PeroxisomeProliferator-Activated Receptors (PPAR) such as the conditions mentionedabove.

The present invention also relates to a process for the preparation ofthe above said novel compounds, their derivatives, their analogs, theirtautomeric forms, their stereoisomers, their polymorphs, theirpharmaceutically acceptable salts or pharmaceutically acceptablesolvates.

The method comprises:

a)

Reacting a compound of formula II

wherein A, X₁, X₂ and Y are defined as above, through a Wittig processwith e.g. (EtO)₂PO(CHZ)(CH₂)_(t)COOR6 (wherein R₆ is an alkyl group), inthe presence of a base such as sodium hydride, EtONa and the like togive a compound of formula III.

wherein A, X₁, X₂, Y, Z and R₆ are defined as above, and wherein t is0-2, andb)

reducing a compound of formula III, wherein A, X₁, X₂, Y, Z, R₆ and tare defined as above with a suitable reagent such a diisobutylaluminumhydride, to give a compound of formula IV.

wherein A, X₁, X₂, Y, Z and t are defined as above, andc)

reacting a compound of IV, wherein A, X₁, X₂, Y, Z and t are defined asabove, with a compound of formula V

wherein Q, Ar, R₁, R₂, R₃, R₄ and m are defined as above, underMitsunobu conditions, using a reagent such astriphenylphosphine/diethylazodicarboxylate and the like to obtain acompound of formula I, wherein A, X₁, X₂, Y, Z, Q, Ar, R₁, R₂, R₃, R₄, nand m are defined as above, except that R₄ is not H, n and m are not 0,and

d)

converting the —OH functionality in a compound of formula IV wherein A,X₁, X₂, Y, Z and t are defined as above to an appropriate leaving group(L) such as p-toluenesulfonate, methanesulfonate, halogen (in examplesby methods according to: Houben-Weyl, Methoden der organischen Chemie,Alkohole III, 6/1b, Thieme Verlag 1984, 4th Ed., pp. 927-939;Comprehensive Organic Transformations. A guide to functional grouppreparations, VCH Publishers 1989, 1^(st) Ed., pp. 353-363), triflateand the like, to give a compound of formula VI

e)

reacting a compound of formula VI

wherein L is a leaving group such as p-toluenesulfonate,methanesulfonate, halogen, triflate and the like and wherein A, X₁, X₂,Y, Z and t are defined as above with a compound of formula V

wherein Q, Ar, R₁, R₂, R₃, R₄ and m are defined as above, to give acompound of formula I wherein A, X₁, X₂, Y, Z, Q, Ar, R₁, R₂, R₃, R₄, nand m are defined as above except that R₄ is not H, n and m are not 0,ore)

reacting a compound of formula VII

wherein A, X₁ and X₂ are defined as above, through a Friedel-Craftsacylation with in example ClOCCHZ(CH₂)_(n)R₇ (wherein n and Z is definedas above and R₇ are halogen or OH), in the presence of a Friedel-Craftscatalysts such as aluminium trichloride and the like, to give a compoundof formula VIII

wherein A, X₁, X₂, Z, R₇ and n are defined as above, andf)

reacting a compound of formula VIII, wherein A, X₁, X₂, Z and R₇ aredefined as above with a Grignard reagents such a MgBrY or a lithiumreagent such as LiY or organozinc reagent such as ZnY, wherein Y isdefined as above, followed by a acidic workup to give a compound offormula IX

wherein A, X₁, X₂, Z, Y, R₇ and n are defined as above, andg)

reacting a compound of IX, wherein A, X₁, X₂, Z, Y, R₇ and n are definedas above, with a compound of formula V

wherein Q, Ar, R₁, R₂, R₃, R₄ and m are defined as above except that mis not 0, under either basic condition e.g. potassium carbonate/acetone(if R₇ is halogen) or Mitsunobu conditions (if R₇ is OH) using a reagentsuch as triphenylphosphine/diethylazodicarboxylate and the like toobtain a compound of formula I, wherein A, X₁, X₂, Y, Z, Q, Ar, R₁, R₂,R₃, R₄, n and m are defined as above, except that R₄ is not H, n and mare not 0, orh)

by chemical or enzymatic saponification of a compound of formula I

wherein A, X₁, X₂, Y, Z, Q, Ar, R₁, R₂, R₃, R₄, n and m are defined asabove, except that R₄ is not H, to obtain a compound of formula I,wherein A, X₁, X₂, Y, Z, Q, Ar, R₁, R₂, R₃, R₄, n and m are defined asabove, except that R₄ is H.i)

Trans-cis or cis-trans isomerization of compounds I, III, IV, VI, and IX(Arai et al., Chem. Rev., 93, pp 23-39, 1993; J. March, Advanced OrganicChemistry, 4^(th) Ed., J. Wiley & Sons, New York 1992, pp. 218, 245,745).

Pharmacological Methods

In Vitro PPAR Alpha and PPAR Gamma Activation Activity.

Principle

The PPAR gene transcription activation assays were based on transienttransfection into human HEK293 cells of two plasmids encoding a chimerictest protein and a reporter protein respectively. The chimeric testprotein was a fusion of the DNA binding domain (DBD) from the yeast GAL4transcription factor to the ligand binding domain (LBD) of the humanPPAR proteins. The PPAR LBD harbored in addition to the ligand bindingpocket also the native activation domain (activating function 2=AF2)allowing the fusion protein to function as a PPAR ligand dependenttranscription factor. The GAL4 DBD will force the fusion protein to bindonly to Gal4 enhancers (of which none existed in HEK293 cells). Thereporter plasmid contained a Gal4 enhancer driving the expression of thefirefly luciferase protein. After transfection, HEK293 cells expressedthe GAL4-DBD-PPAR-LBD fusion protein. The fusion protein will in turnbind to the Gal4 enhancer controlling the luciferase expression, and donothing in the absence of ligand. Upon addition to the cells of a PPARligand, luciferase protein will be produced in amounts corresponding tothe activation of the PPAR protein. The amount of luciferase protein ismeasured by light emission after addition of the appropriate substrate.

Methods

In Vitro Transactivation Assays

Cell culture and transfection: HEK293 cells were grown in DMEM+10% FCS.Cells were seeded in 96-well plates the day before transfection to givea confluency of 50-80% at transfection. A total of 0.8 μg DNA containing0.64 μg pM1α/γLBD, 0.1 μg pCMVβGal, 0.08 μg pGL2Gal4DBD and 0.02 μgpADVANTAGE was transfected per well using FuGene transfection reagentaccording to the manufacturers instructions (Roche). Cells were allowedto express protein for 48 h followed by addition of compound.

Plasmids: Human PPAR α and γ was obtained by PCR amplification usingcDNA synthesized by reverse transcription of mRNA from liver and adiposetissue respectively. Amplified cDNAs were cloned into pCR2.1 andsequenced. The ligand binding domain (LBD) of each PPAR isoform wasgenerated by PCR (PPARα: aa 167—C-terminus; PPARγ: aa 165—C-terminus)and fused to the DNA binding domain (DBD) of the yeast transcriptionfactor GAL4 by subcloning fragments in frame into the vector pM1generating the plasmids pM1αLBD and pM1γLBD. Ensuing fusions wereverified by sequencing. The reporter was constructed by inserting anoligonucleotide encoding five repeats of the GAL4 recognition sequence(5×CGGAGTACTGTCCTCCG(AG)) into the vector pGL2 promotor (Promega)generating the plasmid pGL2(GAL4)₅. pCMVβGal was purchased from Clontechand pADVANTAGE was purchased from Promega.

Luciferase assay: Medium including test compound was aspirated and 100μl PBS incl. 1 mM Mg++ and Ca++ was added to each well. The luciferaseassay was performed using the Lu-cLite kit according to themanufacturers instructions (Packard Instruments). Light emission wasquantified by counting SPC mode on a Packard Instruments top-counter. Tomeasure β-galactosidase activity 25 μl supernatant from eachtransfection lysate was transferred to a new microplate. β-galactosidaseassays were performed in the microwell plates using a kit from Promegaand read in a microplate reader. The β-galactosidase data were used tonormalize (transfection efficiency, cell growth etc.) the luciferasedata.

Compounds: All compounds were dissolved in DMSO and diluted 1:1000 uponaddition to the cells. Compounds were tested in quadruple in fiveconcentrations ranging form 0.01 to 30 μM. Cells were treated withcompound for 24 h followed by luciferase assay. Each compound was testedin three separate experiments. EC₅₀ values were calculated vianon-linear regression using GraphPad PRISM 3.02 (GraphPad Software, SanDiego, Calif.). The results were expressed as means.

TABLE 1 In vitro PPAR alpha and PPAR gamma activation of examplesaccording to the present invention. In vitro activation PPAR α PPAR γExample no EC₅₀, μM % max^(a) EC₅₀, μM % max^(b) 4 3.1 212 0.72 156 90.038 234 0.35 125 27 0.10 185 0.11 99 57 0.38 178 0.70 110 124 0.35 1020.30 83 134 2.90 122 0.89 155 Compounds were tested in at least threeseparate experiments in five concentrations ranging from 0.01 to 30 μM.EC₅₀'s were not calculated for compounds producing transactivation lowerthan 25% at 30 μM. ^(a)Fold activation relative to maximum activationobtained with Wy14643 (approx. 20 fold corresponded to 100%) and with^(b)rosiglitazone (approx. 120 fold corresponded to 100%).

Pharmaceutical Compositions

In another aspect, the present invention includes within its scopepharmaceutical compositions comprising, as an active ingredient, atleast one of the compounds of the general formula I or apharmaceutically acceptable salt thereof together with apharmaceutically acceptable carrier or diluent.

The present compounds may also be administered in combination with oneor more further pharmacologically active substances eg., selected fromantiobesity agents, antidiabetics, antihypertensive agents, agents forthe treatment and/or prevention of complications resulting from orassociated with diabetes and agents for the treatment and/or preventionof complications and disorders resulting from or associated withobesity.

Thus, in a further aspect of the invention the present compounds may beadministered in combination with one or more antiobesity agents orappetite regulating agents.

Such agents may be selected from the group consisting of CART (cocaineamphetamine regulated transcript) agonists, NPY (neuropeptide Y)antagonists, MC4 (melanocortin 4) agonists, orexin antagonists, TNF(tumor necrosis factor) agonists, CRF (corticotropin releasing factor)agonists, CRF BP (corticotropin releasing factor binding protein)antagonists, urocortin agonists, β3 agonists, MSH(melanocyte-stimulating hormone) agonists, MCH (melanocyte-concentratinghormone) antagonists, CCK (cholecystokinin) agonists, serotoninre-uptake inhibitors, serotonin and noradrenaline re-uptake inhibitors,mixed serotonin and noradrenergic compounds, 5HT (serotonin) agonists,bombesin agonists, galanin antagonists, growth hormone, growth hormonereleasing compounds, TRH (thyreotropin releasing hormone) agonists, UCP2 or 3 (uncoupling protein 2 or 3) modulators, leptin agonists, DAagonists (bromocriptin, doprexin), lipase/amylase inhibitors, RXR(retinoid X receptor) modulators or TR β agonists.

In one embodiment of the invention the antiobesity agent is leptin.

In another embodiment the antiobesity agent is dexamphetamine oramphetamine.

In another embodiment the antiobesity agent is fenfluramine ordexfenfluramine.

In still another embodiment the antiobesity agent is sibutramine.

In a further embodiment the antiobesity agent is orlistat.

In another embodiment the antiobesity agent is mazindol or phentermine.

Suitable antidiabetics comprise insulin, GLP-1 (glucagons likepeptide-1) derivatives such as those disclosed in WO 98/08871 to NovoNordisk A/S, which is incorporated herein by reference as well as orallyactive hypoglycaemic agents.

The orally active hypoglycaemic agents preferably comprisesulphonylureas, biguanides, meglitinides, glucosidase inhibitors,glucagon antagonists such as those disclosed in WO 99/01423 to NovoNordisk A/S and Agouron Pharmaceuticals, Inc., GLP-1 agonists, potassiumchannel openers such as those disclosed in WO 97/26265 and WO 99/03861to Novo Nordisk A/S which are incorporated herein by reference, DPP-IV(dipeptidyl peptidase-IV) inhibitors, inhibitors of hepatic enzymesinvolved in stimulation of gluconeogenesis and/or glycogenolysis,glucose uptake modulators, compounds modifying the lipid metabolism suchas antihyperlipidemic agents and antilipidemic agents as HMG CoAinhibitors (statins), compounds lowering food intake, RXR agonists andagents acting on the ATP-dependent potassium channel of the β-cells.

In one embodiment of the invention the present compounds areadministered in combination with insulin.

In a further embodiment the present compounds are administered incombination with a sulphonylurea eg. tolbutamide, glibenclamide,glipizide or glicazide.

In another embodiment the present compounds are administered incombination with a biguanide eg. metformin.

In yet another embodiment the present compounds are administered incombination with a meglitinide eg. repaglinide or senaglinide.

In a further embodiment the present compounds are administered incombination with an α-glucosidase inhibitor eg. miglitol or acarbose.

In another embodiment the present compounds are administered incombination with an agent acting on the ATP-dependent potassium channelof the β-cells eg. tolbutamide, glibenclamide, glipizide, glicazide orrepaglinide.

Furthermore, the present compounds may be administered in combinationwith nateglinide.

In still another embodiment the present compounds are administered incombination with an antihyperlipidemic agent or antilipidemic agent eg.cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin,pravastatin, simvastatin, probucol or dextrothyroxine.

In a further embodiment the present compounds are administered incombination with more than one of the above-mentioned compounds eg. Incombination with a sulphonylurea and metformin, a sulphonylurea andacarbose, repaglinide and mefformin, insulin and a sulphonylurea,insulin and mefformin, insulin, insulin and lovastatin, etc.

Furthermore, the present compounds may be administered in combinationwith one or more antihypertensive agents. Examples of antihypertensiveagents are β-blockers such as alprenolol, atenolol, timolol, pindolol,propranolol and metoprolol, ACE (angiotensin converting enzyme)inhibitors such as benazepril, captopril, enalapril, fosinopril,lisinopril, quinapril and ramipril, calcium channel blockers such asnifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazemand verapamil, and α-blockers such as doxazosin, urapidil, prazosin andterazosin. Further reference can be made to Remington: The Science andPractice of Pharmacy, 19^(th) Edition, Gennaro, Ed., Mack PublishingCo., Easton, Pa., 1995.

It should be understood that any suitable combination of the compoundsaccording to the invention with one or more of the above-mentionedcompounds and optionally one or more further pharmacologically activesubstances are considered to be within the scope of the presentinvention.

Pharmaceutical compositions containing a compound of the presentinvention may be prepared by conventional techniques, e.g. as describedin Remington: The Science and Practise of Pharmacy, 19^(th) Ed., 1995.The compositions may appear in conventional forms, for example capsules,tablets, aerosols, solutions, suspensions or topical applications.

Typical compositions include a compound of formula I or apharmaceutically acceptable acid addition salt thereof, associated witha pharmaceutically acceptable excipient which may be a carrier or adiluent or be diluted by a carrier, or enclosed within a carrier whichcan be in the form of a capsule, sachet, paper or other container. Inmaking the compositions, conventional techniques for the preparation ofpharmaceutical compositions may be used. For example, the activecompound will usually be mixed with a carrier, or diluted by a carrier,or enclosed within a carrier which may be in the form of a ampoule,capsule, sachet, paper, or other container. When the carrier serves as adiluent, it may be solid, semi-solid, or liquid material which acts as avehicle, excipient, or medium for the active compound. The activecompound can be adsorbed on a granular solid container for example in asachet. Some examples of suitable carriers are water, salt solutions,alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil,peanut oil, olive oil, gelatine, lactose, terra alba, sucrose,cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin,acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid,fatty acids, fatty acid amines, fatty acid monoglycerides anddiglycerides, pentaerythritol fatty acid esters, polyoxyethylene,hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrieror diluent may include any sustained release material known in the art,such as glyceryl monostearate or glyceryl distearate, alone or mixedwith a wax. The formulations may also include wetting agents,emulsifying and suspending agents, preserving agents, sweetening agentsor flavouring agents. The formulations of the invention may beformulated so as to provide quick, sustained, or delayed release of theactive ingredient after administration to the patient by employingprocedures well known in the art.

The pharmaceutical compositions can be sterilized and mixed, if desired,with auxiliary agents, emulsifiers, salt for influencing osmoticpressure, buffers and/or colouring substances and the like, which do notdeleteriously react with the active compounds.

The route of administration may be any route, which effectivelytransports the active compound to the appropriate or desired site ofaction, such as oral, nasal, pulmonary, transdermal or parenteral e.g.rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular,intranasal, ophthalmic solution or an ointment, the oral route beingpreferred.

If a solid carrier is used for oral administration, the preparation maybe tabletted, placed in a hard gelatin capsule in powder or pellet formor it can be in the form of a troche or lozenge. If a liquid carrier isused, the preparation may be in the form of a syrup, emulsion, softgelatin capsule or sterile injectable liquid such as an aqueous ornon-aqueous liquid suspension or solution.

For nasal administration, the preparation may contain a compound offormula I dissolved or suspended in a liquid carrier, in particular anaqueous carrier, for aerosol application. The carrier may containadditives such as solubilizing agents, e.g. propylene glycol,surfactants, absorption enhancers such as lecithin (phosphatidylcholine)or cyclodextrin, or preservatives such as parabenes.

For parenteral application, particularly suitable are injectablesolutions or suspensions, preferably aqueous solutions with the activecompound dissolved in polyhydroxylated castor oil.

Tablets, dragees, or capsules having talc and/or a carbohydrate carrieror binder or the like are particularly suitable for oral application.Preferable carriers for tablets, dragees, or capsules include lactose,corn starch, and/or potato starch. A syrup or elixir can be used incases where a sweetened vehicle can be employed.

A typical tablet which may be prepared by conventional tablettingtechniques may contain:

Core: Active compound (as free compound or salt thereof)   5 mgColloidal silicon dioxide (Aerosil) 1.5 mg Cellulose, microcryst.(Avicel)  70 mg Modified cellulose gum (Ac-Di-Sol) 7.5 mg Magnesiumstearate Ad. Coating: HPMC approx.   9 mg *Mywacett 9-40 T approx. 0.9mg *Acylated monoglyceride used as plasticizer for film coating.

The compounds of the invention may be administered to a mammal,especially a human in need of such treatment, prevention, elimination,alleviation or amelioration of diseases related to the regulation ofblood sugar.

Such mammals include also animals, both domestic animals, e.g. householdpets, and non-domestic animals such as wildlife.

The compounds of the invention are effective over a wide dosage range.For example, in the treatment of adult humans, dosages from about 0.05to about 100 mg, preferably from about 0.1 to about 100 mg, per day maybe used. A most preferable dosage is about 0.1 mg to about 70 mg perday. In choosing a regimen for patients it may frequently be necessaryto begin with a dosage of from about 2 to about 70 mg per day and whenthe condition is under control to reduce the dosage as low as from about0.1 to about 10 mg per day. The exact dosage will depend upon the modeof administration, on the therapy desired, form in which administered,the subject to be treated and the body weight of the subject to betreated, and the preference and experience of the physician orveterinarian in charge.

Generally, the compounds of the present invention are dispensed in unitdosage form comprising from about 0.1 to about 100 mg of activeingredient together with a pharmaceutically acceptable carrier per unitdosage.

Usually, dosage forms suitable for oral, nasal, pulmonary or transdermaladministration comprise from about 0.001 mg to about 100 mg, preferablyfrom about 0.01 mg to about 50 mg of the compounds of formula I admixedwith a pharmaceutically acceptable carrier or diluent.

Any novel feature or combination of features described herein isconsidered essential to this invention.

EXAMPLES

The process for preparing compounds of formula I, and preparationscontaining them, is further illustrated in the following examples, whichhowever, are not to be construed as limiting.

The structures of the compounds are confirmed by either elementalanalysis (MA) nuclear magnetic resonance (NMR) or mass spectrometry(MS). NMR shifts (δ) are given in parts per million (ppm) and onlyselected peaks are given. Mp is melting point and is given in ° C.Column chromatography was carried out using the technique described byW. C. Still et al, J. Org. Chem. 1978, 43, 2923-2925 on Merck silica gel60 (Art 9385). Compounds used as starting materials are either knowncompounds or compounds which can readily be prepared by methods knownper se.

Abbrevations: THF: tetrahydrofuran DIBAL-H: diisobutylaluminum hydrideNa₂SO₄: sodium sulfate MgSO₄: magnesium sulfate DMSO: dimethylsulfoxideCDCl₃: deuterated chloroform DMF: N,N-dimethylformamide HCl:hydrochloric acid DME: 1,2-dimethoxyethane min: minutes h: hours

Example 1

(E)-(S)-Ethyl3-[4-(3-biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-ethoxy-propionate

a)

Sodium (1.75 g, 73.4 mmol) was added to ethanol (45 ml) at 20° C. andthe mixture stirred until the metal had fully reacted. Triethylphosphonoacetate (14.69 g, 73.4 mmol) was added, the mixture stirred for5 min., then 4-acetylbiphenyl (12.00 g, 61.1 mmol) was added to thestirred solution. The mixture was stirred at room temperature for 24 h,the resulting suspension filtered, and the filter-cake collected andrecrystallised from ethanol to give (E)-3-biphenyl-4-yl-but-2-enoic acidethyl ester as white crystals; 5.73 g (36%)

¹H NMR (300 MHz, CDCl₃) δ: 1.32 (3H, t), 2.62 (3H, d), 4.21 (2H, q), 6.2(1H, d), 7.31-7.65 (9H, m). MS: 267 (M⁺), 266(100%), 221, 194, 178.Microanalysis Calculated % C, 81.00; H, 7.0. Found C, 80.86; H, 6.90.

b)

A 1M solution of DIBAL-H in toluene (40 ml, 40 mmol) was added dropwiseat −70° C. over 20 min. to a stirred solution of3-biphenyl-4-yl-but-2-enoic acid ethyl ester (2.66 g, 10.0 mmol) in dryTHF (100 ml) and the mixture stirred for 30 min. Methanol (2 ml) wasadded, followed by saturated aqueous Rochelle's salt (100 ml), and theresulting mixture extracted with ethyl acetate (200 ml), separated andthe organic phase washed with brine, dried (Na₂SO₄), evaporated anddried in vacuo yielding (E)-3-biphenyl-4-yl-but-2-en-1-ol as colorlesscrystals: 1.94 g (86%)

¹H NMR (300 MHz, CDCl₃) δ: 1.40 (1H, br s), 2.12 (3H, d), 4.45 (2H, dd),6.05 (1H, dt), 7.35-7.7 (9H, m). MS: 225 (M⁺), 224(100%), 209, 181,165.Microanalysis Calculated % C, 86.00; H, 7.00. Found C, 85.67; H, 7.29.

c)

Diethyl azodicarboxylate (0.346 ml, 2.2 mmol) was added at 0° C. to astirred solution of triphenyl-phosphine (0.656 g, 2.2 mmol) and(E)-3-biphenyl-4-yl-but-2-en-1-ol (0.270 g, 1.2 mmol) in dry THF (20 ml)and the mixture stirred for 5 min. A solution of (S)-ethyl2-ethoxy-3-(4-hydroxy-phenyl)-propionate (0.238 g, 1.0 mmol) in dry THF(10 ml) was added, the mixture allowed to warm to room temperature, andstirring continued for 48 h. The resulting mixture was evaporated invacuo and the residue purified by column chromatography on silica gel(20% ethyl acetate in n-heptane) to give (E)-(S)-ethyl3-[4-(3-biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-ethoxy-propionate as anoil; 0.288 g (65%).

¹H NMR (300 MHz, CDCl₃) δ: 1.13-1.25 (6H, m), 2.13 (3H, d), 2.94 (2H,d), 3.29-3.37 (1H, m), 3.54-3.61 (1H, m), 3.97 (1H, t), 4.1 (2H, q),4.70 (2H, d), 6.11 (1H, dt), 6.86 (2H, d), 7.16 (2H, d), 7.25-7.63 (9H,m).

Example 2

(E)-(S)-3-[4-(3-Biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-ethoxy-propionicacid

Sodium hydroxide (1M, 0.45 ml, 0.45 mmol) was added to a solution of(E)-(S)-ethyl3-[4-(3-biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-ethoxy-propionate(example 1) (0.100 g, 0.225 mmol) in ethanol (20 ml) and the mixturestirred at 70° C. for 2.5 h. After cooling to room temperature theresulting mixture was partitioned between water (50 ml) and ethylacetate and the aqueous phase collected. The aqueous phase was acidifiedwith 1N hydrochloric acid (5 ml) and extracted with ethyl acetate (100ml), and the organic phase collected, washed with brine, dried (Na₂SO₄)and evaporated to give(E)-(S)-3-[4-(3-biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-ethoxy-propionicacid as a white solid; 0.014 g (15%).

¹H NMR (300 MHz, CDCl₃) δ: 1.19 (3H, t), 2.63 (3H, d), 2.93 (1H, dd),3.1 (1H, dd), 3.4-3.65 (2H, m), 4.1 (2H, q), 4.72 (2H, d), 6.1 (1H, dt),6.9 (2H, d), 7.2 (2H, d), 7.35-7.60 (9H, m).

Example 3

(E)-(S)-3-{4-[3-(4′-Bromo-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid ethyl ester

a)

(E)-3-(4′-Bromo-biphenyl-4-yl)-but-2-enoic acid ethyl ester was preparedfrom 4-(4-bromophenyl)acetophenone (12.0 g, 0.044 mol), sodium (1.25 g,0.052 mol) and triethyl phosphonoacetate (11.73 g, 0.052 mol) by aprocedure analogous to that described in example 1a yielding 11.97 g(80%).

¹H NMR (300 MHz, CDCl₃) δ: 1.32 (3H, t), 2.61 (3H, d), 4.23 (2H, q),6.19 (1H, d), 7.40-7.58 (8H, m).

b)

(E)-3-(4′-bromo-biphenyl-4-yl)-but-2-en-1-ol was prepared from(E)-3-(4′-bromo-biphenyl-4-yl)-but-2-enoic acid ethyl ester (3.45 g,10.0 mmol) and DIBAL-H (1M in toluene, 40 ml, 40 mmol) by a procedureanalogous to that described in example 1b, yielding 1.68 g (55%).

¹H NMR (300 MHz, CDCl₃) δ: 2.14 (3H, d), 4.4 (2H, t), 6.05 (1H, dt),7.45-7.55 (8H, m),

c)

The title compound was prepared from(E)-3-(4′-bromo-biphenyl-4-yl)-but-2-en-1-ol (0.364 g, 1.2 mmol),triphenylphosphine (0.328 g, 1.3 mmol), diethyl azodicarboxylate (0.173ml, 1.1 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxy-phenyl)-propionate(0.238 g, 1.0 mmol) by a procedure analogous to that described inexample 1c, yielding 0.180 g (34%) of(E)-(S)-3-{4-[3-(4′-bromo-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid ethyl ester.

¹H NMR (300 MHz, CDCl₃) δ: 1.15-1.25 (6H, m), 2.15 (3H, d), 2.95 (2H, d)3.29-3.4 (1H, m), 3.5-3.65 (1H, m), 3.96 (1H, t), 4.15 (2H, q), 4.75(2H, dd), 6.11 (1H, dt), 6.85 (2H, d), 7.14 (2H, d), 7.4-7.55 (8H, m).

Example 4

(E)-(S)-3-{4-[3-(4′-Bromo-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid

The title compound was prepared from(E)-(S)-3-{4-[3-(4′-bromo-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid ethyl ester (example 3) (0.150 g, 0.29 mmol) and sodium hydroxide(1M, 0.45 ml, 0.45 mmol) by a procedure analogous to that described inexample 2 yielding 0.180 g (34%) of(E)-(S)-3-{4-[3-(4′-bromo-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid ethyl ester.

¹H NMR (300 MHz, CDCl₃) δ: 1.14 (3H, t), 2.13 (3H, d), 2.86-3.10 (2H,m), 3.37-3.45 (1H, m), 3.55-3.65 (1H, m), 4.05 (2H, q), 4.70 (2H, dd),6.12 (1H, dt), 6.9 (2H, d), 7.18 (2H, d), 7.4-7.60 (8H, m).

Example 5

(E)-(S)-2-Ethoxy-3-{4-[3-(4-phenoxy-phenyl)-but-2-enyloxy]-phenyl}-propionicacid ethyl ester

The title compound was prepared from 4-phenoxyacetophenone (12.0 g,0.056 mol) by a sequence analogous to that described in example 3,yielding 0.190 g (41%) of(E)-(S)-2-ethoxy-3-{4-[3-(4-phenoxy-phenyl)-but-2-enyloxy]-phenyl}-propionicacid ethyl ester.

¹H NMR (300 MHz, CDCl₃) δ: 1.2 (6H, m), 2.12 (3H, s), 2.97 (2H, d),3.30-3.42 (1H, m), 3.59-3.70 (1H, m), 3.98 (1H, t), 4.15 (2H, q), 4.73(2H, dd), 6.05 (1H, dt), 6.85-7.45 (13H, m).

Example 6

(E)-(S)-2-Ethoxy-3-{4-[3-(4-phenoxy-phenyl)-but-2-enyloxy]-phenyl}-propionicacid

The title compound was prepared from(E)-(S)-2-ethoxy-3-{4-[3-(4-phenoxy-phenyl)-but-2-enyloxy]-phenyl}-propionicacid ethyl ester (example 5) (0.170 g, 0.37 mmol) and sodium hydroxide(1M, 0.74 ml, 0.74 mmol) by a procedure analogous to that described inexample 2 yielding 0.136 g (85%) of(E)-(S)-2-ethoxy-3-{4-[3-(4-phenoxy-phenyl)-but-2-enyloxy]-phenyl}-propionicacid.

¹H NMR (300 MHz, CDCl₃) δ: 1.14 (3H, t), 2.13 (3H, d), 2.86-3.10 (2H,m), 3.38-3.45 (1H, m), 3.55-3.65(1H, m), 4.05 (2H, q), 4.70 (2H, dd),6.12 (1H, dt), 6.9 (2H, d), 7.18 (2H, d), 7.4-7.60 (8H, m).

Example 7

(E)-(S)-2-Ethoxy-3-(4-{3-[4-(4-methoxy-phenoxy)-phenyl]-but-2-enyloxy}-phenyl)-propionicacid ethyl ester

The title compound was prepared from 4-(4-methoxyphenoxy)acetophenone(2.63 g, 0.011 mol) by a sequence analogous to that described in example3 yielding 0.200 g (41%) of(E)-(S)-2-ethoxy-3-(4-{3-[4-(4-methoxy-phenoxy)-phenyl]-but-2-enyloxy}-phenyl)-propionicacid ethyl ester.

¹H NMR (300 MHz, CDCl₃) δ: 1.15-1.23 (6H, m), 2.12 (3H, s), 2.97 (2H,d), 3.30-3.40 (1H, m), 3.57-3.65 (1H, m), 3.80 (3H, s), 3.98 (1H, t),4.18 (2H, q), 4.63 (2H, dd), 5.97-6.05 (1H, m), 6.85-6.96 (8H, m), 7.15(2H, d), 7.35 (2H, d). MS 490 (M⁺), 417, 359 (100%), 269.

Example 8

(E)-(S)-2-Ethoxy-3-(4-{3-[4-(4-methoxy-phenoxy)-phenyl]-but-2-enyloxy}-phenyl)-propionicacid

The title compound was prepared from(E)-(S)-2-ethoxy-3-(4-{3-[4-(4-methoxy-phenoxy)-phenyl]-but-2-enyloxy}-phenyl)-propionicacid ethyl ester (example 7) (0.176 g, 0.36 mmol) and sodium hydroxide(1M, 0.74 ml, 0.74 mmol) by a procedure analogous to that described inexample 2 yielding 0.140 g (84%) of(E)-(S)-2-ethoxy-3-(4-{3-[4-(4-methoxy-phenoxy)-phenyl]-but-2-enyloxy}-phenyl)-propionicacid.

¹H NMR (300 MHz, CDCl₃) δ: 1.15 (3H, t), 2.1 (3H, s), 2.9-3.1 (2H, m),3.36-3.43 (1H, m), 3.55-3.64 (1H, m), 3.78 (3H, s), 4.00 (1H, dd), 4.70(2H, dd), 6.0 (1H, dt), 6.8-6.9 (8H, m), 7.19 (2H, d), 7.35 (2H, d). MS462 (M⁺)(100%), 436, 359, 252.

Example 9

(E)-(S)-2-Ethoxy-3-{4-[3-(9H-fluoren-2-yl)-but-2-enyloxy]-phenyl}-propionicacid ethyl ester

The title compound was prepared from 2-acetylfluorene (12.0 g, 0.058mmol) by a sequence analogous to that described in example 3 yielding0.200 g (41%) of(E)-(S)-2-ethoxy-3-{4-[3-(9H-fluoren-2-yl)-but-2-enyloxy]-phenyl}-propionicacid ethyl ester.

¹H NMR (300 MHz, CDCl₃) δ: 1.16-1.22 (6H, m), 2.2 (3H, s), 2.96 (2H, d),3.30-3.40 (1H, m), 3.51-3.65 (1H, m), 3.9 (2H, s), 3.98 (1H, t), 4.15(2H, q), 4.75 (2H, d), 6.04-6.13 (1H, m), 6.88 (2H, d), 7.17 (2H, d),7.3-7.8 (7H, m). MS 456 (M⁺), 410, 325 (100%), 238. MicroanalysisCalculated % C, 78.92; H, 7.06. Found C, 78.72; H, 7.30.

Example 10

(E)-(S)-2-Ethoxy-3-{4-[3-(9H-fluoren-2-yl)-but-2-enyloxy]-phenyl}-propionicacid

The title compound was prepared from(E)-(S)-2-ethoxy-3-{4-[3-(9H-fluoren-2-yl)-but-2-enyloxy]-phenyl}-propionicacid ethyl ester (example 9) (0.230 g, 0.504 mol) and sodium hydroxide(1M, 1.008 ml, 1.008 mmol) by a procedure analogous to that described inexample 2 yielding 0.140 g (84%) of(E)-(S)-2-ethoxy-3-{4-[3-(9H-fluoren-2-yl)-but-2-enyloxy]-phenyl}-propionicacid.

¹H NMR (300 MHz, CDCl₃) δ: 1.20 (3H, t), 2.18 (3H, s), 2.9-3.15 (2H, m),3.4-3.6 (2H, m), 3.87 (2H, s), 4.05 (1H, dd), 4.75 (2H, d), 6.11 (1H,dt), 6.88 (2H, d), 7.17 (2H, d), 7.3-7.8 (7H, m).

Example 11

(E)-(S)-3-{4-[3-(3,4-Dimethoxy-phenyl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid ethyl ester

The title compound was prepared from 3,4-dimethoxyacetophenone (10.00 g,0.055 mol) by a sequence analogous to that described in example 3yielding 0.160 g (31%) of(E)-(S)-3-{4-[3-(3,4-dimethoxy-phenyl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid ethyl ester.

¹H NMR (300 MHz, CDCl₃) δ: 1.1-1.19 (6H, m), 2.17 (3H, s), 2.98 (2H, d),3.37-3.45 (1H, m), 3.58-3.65 (1H, m), 3.9 (6H, ds), 4.02 (1H, t), 4.15(2H, q), 4.7 (2H, d), 6.0 (1H, dt), 6.81-6.86 (3H, m), 7.0 (2H, d), 7.15(2H, d). MS 428 (M⁺), 382, 355,297 (100%), 207.

Example 12

(E)-(S)-3-{4-[3-(3,4-Dimethoxy-phenyl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid

The title compound was prepared from(E)-(S)-3-{4-[3-(3,4-dimethoxy-phenyl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid ethyl ester (example 11) (0.150 g, 0.350 mmol) and sodium hydroxide(1M, 1.05 ml, 1.05 mmol) by a procedure analogous to that described inexample 2 yielding 0.120 g (86%) of(E)-(S)-3-{4-[3-(3,4-dimethoxy-phenyl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid.

¹H NMR (300 MHz, CDCl₃) δ: 1.15 (3H, t), 2.15 (3H, s), 2.9-3.15 (2H, m),3.40-3.48 (1H, m), 3.56-3.63 (1H, m), 3.9 (6H, ds), 4.08 (1H, dd), 4.75(2H, d), 6.01 (1H, dt), 6.80-6.91 (3H, m), 7.0 (2H, d), 7.15 (2H, d).

Example 13

(E)-(S)-3-{4-[3-(3,5-Bis-trifluoromethyl-phenyl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid ethyl ester

The title compound was prepared from3,5-bis(trifluoromethyl)acetophenone (5.12 g, 0.02 mol) by a sequenceanalogous to that described in example 3 yielding 0.370 g (73%) of(E)-(S)-3-{4-[3-(3,5-bis-trifluoromethyl-phenyl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid ethyl ester.

¹H NMR (300 MHz, CDCl₃) δ: 1.1-1.25 (6H, m), 2.20 (3H, s), 2.97 (2H, d),3.3-3.4 (1H, m), 3.62-3.7 (1H, m), 4.0 (1H, t), 4.15 (2H, q), 4.75 (2H,d), 6.2 (1H, dt), 6.85 (2H, d), 7.2 (2H, d), 7.78 (1H, br s), 7.87 (2H,br s). MS 504 (M⁺), 458, 431(100%), 373 , 267, 192

Example 14

(E)-(S)-3-{4-[3-(3,5-Bis-trifluoromethyl-phenyl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid

The title compound was prepared from(E)-(S)-3-{4-[3-(3,5-bis-trifluoromethyl-phenyl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid ethyl ester (example 13) (0.200 g, 0.396 mmol) and sodium hydroxide(1M, 0.792 ml, 0.792 mmol) by a procedure analogous to that described inexample 2 yielding 0.150 g (79%) of(E)-(S)-3-{4-[3-(3,5-bis-trifluoromethyl-phenyl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid.

¹H NMR (300 MHz, CDCl₃) δ: 1.12 (3H, t), 2.18 (3H, s), 2.9 (1H, dd), 3.1(1H, dd), 3.34-3.42 (1H, m), 3.5-3.65 (1H, m), 4.0 (1H, dd), 4.7 (2H,d), 6.11 (1H, dt), 6.83 (2H, d), 7.19 (2H, d) 7.72 (1H, br s), 7.83 (2H,br s).

Example 15

(E)-(S)-3-[4-(3-Biphenyl-4-yl-allyloxy)-phenyl]-2-ethoxy-propionic acidethyl ester

The title compound was prepared from 3-biphenyl-4-yl-acrylic acid ethylester (2.5 g, 0.01 mol) by a sequence analogous to that described inexample 3b-c yielding 0.370 g (73%) of(E)-(S)-3-[4-(3-biphenyl-4-yl-allyloxy)-phenyl]-2-ethoxy-propionic acidethyl ester.

¹H NMR (200 MHz, CDCl₃) δ: 1.1-1.25 (6H, m), 2.97 (2H, d), 3.3-3.4 (1H,m), 3.52-3.7 (1H, m), 4.0 (1H, t), 4.15 (2H, q), 4.75 (2H, dd), 6.35-6.5(1H, dt), 6.75 (1H, d), 6.87 (2H, d), 7.15 (2H, d), 7.4-7.65 (9H, m).

Example 16

(E)-(S)-3-[4-(3-Biphenyl-4-yl-allyloxy)-phenyl]-2-ethoxy-propionic acid

The title compound was prepared from(E)-(S)-3-[4-(3-biphenyl-4-yl-allyloxy)-phenyl]-2-ethoxy-propionic acidethyl ester (example 15) (0.200 g, 0.464 mmol) and sodium hydroxide (1M,0.928 ml, 0.928 mmol) by a procedure analogous to that described inexample 2 yielding 0.043 g (23%) of(E)-(S)-3-[4-(3-biphenyl-4-yl-allyloxy)-phenyl]-2-ethoxy-propionic acid.

¹H NMR (300 MHz, CDCl₃) δ: 1.15 (3H, t), 2.9 (1H, dd), 3.12 (1H, dd)3.45-3.55 (2H, m), 3.84-3.96 (2H, m), 4.1 (1H, dd), 4.7 (2H, d),6.35-6.5 (1H, dt), 6.78 (1H, d), 6.88 (2H, d), 7.15 (2H, d) 7.4-7.6 (9H,m).

Example 17

(E)-(S)-2-Ethoxy-3-[4-(3-naphthalen-2-yl-but-2-enyloxy)-phenyl]-propionicacid ethyl ester

The title compound was prepared from 2-acetonaphthone (10.0 g, 0.06 mol)by a sequence analogous to that described in example 3 yielding 0.190 g(38%) of(E)-(S)-2-ethoxy-3-[4-(3-naphthalen-2-yl-but-2-enyloxy)-phenyl]-propionicacid ethyl ester.

¹H NMR (200 MHz, CDCl₃) δ: 1.1-1.2 (6H, m), 2.20 (3H, s), 2.95 (2H, d),3.3-3.4 (1H, m), 3.52-3.65 (1H, m), 3.95 (1H, t), 4.15 (2H, q), 4.76(2H, d), 6.2 (1H, t), 6.85 (2H, d), 7.15 (2H, d), 7.35-7.42 (2H, m), 7.6(1H, dd), 7.75-7.85 (4H, m).

Example 18

(E)-(S)-2-Ethoxy-3-[4-(3-naphthalen-2-yl-but-2-enyloxy)-phenyl]-propionicacid

The title compound was prepared from(E)-(S)-2-ethoxy-3-[4-(3-naphthalen-2-yl-but-2-enyloxy)-phenyl]-propionicacid ethyl ester (example 17) (0.165 g, 0.394 mmol) and sodium hydroxide(1M, 0.789 ml, 0.789 mmol) by a procedure analogous to that described inexample 2 yielding 0.030 g (19%) of(E)-(S)-2-ethoxy-3-[4-(3-naphthalen-2-yl-but-2-enyloxy)-phenyl]-propionicacid.

¹H NMR (400 MHz, CDCl₃) δ: 1.13 (3H, t), 2.18 (3H, s), 2.95 (1H, dd),3.05 (1H, dd), 3.3-3.45 (1H, m), 3.65-3.63 (1H, m), 3.95 (1H, dd), 4.72(2H, d), 6.15 (1H, t), 6.84 (2H, d), 7.14 (2H, d), 7.35-7.45 (2H, m),7.6 (1H, d), 7.7-7.8 (4H, m).

Example 19

(E)-(S)-2-Ethoxy-3-[4-(3-pyridin-2-yl-but-2-enyloxy)-phenyl]-propionicacid ethyl ester

The title compound was prepared from 2-acetylpyridine (9.6 g, 0.08 mol)by a sequence analogous to that described in example 3 yielding 0.230 g(23%) of(E)-(S)-2-ethoxy-3-[4-(3-pyridin-2-yl-but-2-enyloxy)-phenyl]-propionicacid ethyl ester.

¹H NMR (400 MHz, CDCl₃) δ: 1.1-2.5 (6H, m), 2.21 (3H, s), 2.97 (2H, d),3.3-3.4 (1H, m), 3.58-3.64 (1H, m), 3.97 (1H, t), 4.15 (2H, q), 4.78(2H, d), 6.65 (1H, t), 6.85 (2H, d), 7.05-7.15 (3H, m), 7.42 (2H, d),7.6 (1 H, dd), 8,52 (1H, d).

Example 20

(E)-(S)-2-Ethoxy-3-[4-(3-pyridin-2-yl-but-2-enyloxy)-phenyl]-propionicacid

The title compound was prepared from(E)-(S)-2-ethoxy-3-[4-(3-pyridin-2-yl-but-2-enyloxy)-phenyl]-propionicacid ethyl ester (example 19) (0.220 g, 0.595 mmol) and sodium hydroxide(1M, 1.19 ml, 1.19 mmol) by a procedure analogous to that described inexample 2 yielding 0.200 g (98%) of(E)-(S)-2-ethoxy-3-[4-(3-pyridin-2-yl-but-2-enyloxy)-phenyl]-propionicacid.

¹H NMR (300 MHz, CDCl₃) δ: 1.2 (3H, t), 2.1 (3H, s), 2.7-2.85 (1H, m),3.0-3.25 (2H, m), 3.5-3.6 (1H, m), 3.8-3.92 (1H, m), 4.6 (2H, d), 6.5(1H, t), 6.75 (2H, d), 7.1-7.2 (3H, m), 7.35 (1H, d), 7.6 (1H, t), 8,5(1H, d).

Example 21

(E)-(S)-3-{4-[3-(3,5-Bis-benzyloxy-phenyl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid ethyl ester

The title compound was prepared from 3,5-dibenzyloxyacetophenone (6.64g, 0.02 mol) by a sequence analogous to that described in example 3yielding 0.460 g (53%) of(E)-(S)-3-{4-[3-(3,5-bis-benzyloxy-phenyl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid ethyl ester.

¹H NMR (300 MHz, CDCl₃) δ: 1.1-1.21 (6H, m), 2.14 (3H, s), 2.95 (2H, d)3.28-3.41 (1H, m), 3.51-3.65 (1H, m), 3.94 (1H, t), 4.12 (2H, q), 4.7(2H, d), 5.05 (4H, s), 6.05 (1H, t), 6.53-6.57 (1H, m), 6.67 (2H, d),6.85 (2H, d), 7.12 (2H, d), 7.3-7.45 (10H, m).

Example 22

(E)-(S)-3-{4-[3-(3,5-Bis-benzyloxy-phenyl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid

The title compound was prepared from(E)-(S)-3-{4-[3-(3,5-bis-benzyloxy-phenyl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid ethyl ester (example 21) (0.430 g, 0.741 mmol) and sodium hydroxide(1M, 1.5 ml, 1.5 mmol) by a procedure analogous to that described inexample 2 yielding 0.300 g (73%) of(E)-(S)-3-{4-[3-(3,5-bis-benzyloxy-phenyl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid.

¹H NMR (300 MHz, CDCl₃) δ: 1.15 (3H, t), 2.1 (3H, s), 2.95 (1H, dd),3.05 (1H, dd), 3.36-3.44 (1H, m), 3.57-3.65 (1H, m), 4.05 (1H, dd), 4.68(2H, d), 5.05 (4H, s), 6.05 (1H, t), 6.52 (1H, m), 6.65 (2H, d), 6.85(2H, d), 7.15 (2H, d), 7.3-7.45 (10H, m).

Example 23

(E)-(S)-2-Ethoxy-3-[4-(3-naphthalen-2-yl-allyloxy)-phenyl]-propionicacid ethyl ester

a)

Triethyl phosphonoacetate (8.9 g, 40.0 mmol) was added at 0° C. over aperiod of 10 min. to a stirred suspension of sodium hydride (60% in oil,1.44 g, 36.0 mmol) in dry THF (145 mL). After stirring at 0° C. for 15min. a solution of 2-naphthaldehyde (3.12 g, 20.0 mmol) in dry THF (15mL) was added, the mixture slowly warmed to room temperature, andstirring continued for 16 h. The reaction mixture was quenched withwater (100 mL) and acidified to pH 6 with 1N hydrochloric acid.Additional water (200 mL) was added, the organic phase separated, andthe aqueous phase further extracted with ethyl acetate (300 mL). Thecombined organic phases were washed with water (200 mL×3), dried(MgSO₄), filtered and concentrated in vacuo to give 6.5 g of crude(E)-3-naphthalen-2-yl-acrylic acid ethyl ester.

b)

Crude (E)-3-naphthalen-2-yl-acrylic acid ethyl ester (4.5 g, 20.0 mmol)was reduced by a procedure analogous to that described in example 1b.The product was purified by flash column chromatography to give 3.1 g(86%) of (E)-3-naphthalen-2-yl-prop-2-en-1-ol.

c)

Under an atmosphere of nitrogen, (E)-3-naphthalen-2-yl-prop-2-en-1-ol(190 mg, 0.8 mmol), tributylphosphine (323 mg, 1.6 mmol) and(S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (184 mg,1.0 mmol) were successively dissolved in dry benzene (20 mL). Solid1,1′-(azodicarbonyl) dipiperidine (403 mg, 1.6 mmol) was added at 0° C.with stirring. After 10 min. the reaction was warmed to room temperatureand the stirring continued for 1 h. The reaction mixture wasconcentrated in vacuo and the product purified by flash columnchromatography, eluting with heptane/ethyl acetate (3:2), to give 180 mg(55%) of the title compound.

¹H NMR (CDCl₃, 300 MHz) δ: 1.15 (t, 3H), 1,22 (t, 3H), 2.95 (d, 2H),3.28-3.40 (m, 1H), 3.55-3.65 (m, 1H), 3.96 (t, 1H), 4.15 (q, 2H), 4.72(dd, 2H), 6.53 (dt, 1H), 6.83-6.93 (m, 3H), 7.18 (d, 2H), 7.40-7.50 (m,2H), 7.13 (dd, 1H), 7.72-7.85 (m, 4H).

Example 24

(E)-(S)-2-Ethoxy-3-[4-(3-naphthalen-2-yl-allyloxy)-phenyl]-propionicacid

(E)-(S)-2-Ethoxy-3-[4-(3-naphthalen-2-yl-allyloxy)-phenyl]-propionicacid ethyl ester (example 23) (170 mg, 0.42 mmol) was dissolved inethanol (20 mL) at 35° C. and sodium hydroxide (1N, 2.1 mL, 2.1 mmol)added. The mixture was stirred at 35° C. for 1 h, the ethanol evaporatedin vacuo and the mixture acidified to pH 1 with 1N hydrochloric acid.The product was isolated by extraction with ethyl acetate (30 mL×2). Thecombined organic phases were dried (MgSO₄), filtered and evaporated togive 155 mg (98%) of the title compound as crystals.

¹H NMR (CDCl₃, 300 MHz) δ: 1.18 (t, 3H), 2.90-3.12 (m, 2H), 3.35-3.48(m, 1H), 3.55-3.68 (m, 1H), 4.03 (q, 1H), 4.70 (dd, 2H), 6.52 (dt, 1H),6.80-6.95 (m, 3H), 7.18 (d, 2H), 7.40-7.48 (m, 2H), 7.60 (dd, 1H),7.70-7.80 (m, 4H).

Example 25

(E)-(S)-2-Ethoxy-3-{4-[3-(3-phenoxy-phenyl)-allyloxy]-phenyl}-propionicacid ethyl ester

The title compound was prepared from 3-phenoxybenzaldehyde (4.0 g, 20.0mmol) by a sequence analogous to that described in example 23.

¹H NMR (CDCl₃, 300 MHz) δ: 1.15 (t, 3H), 1,22 (t, 3H), 2.95 (d, 2H),3.30-3.40 (m, 1H), 3.55-3.68 (m, 1H), 3.98 (t, 1H), 4.15 (q, 2H), 4.72(dd, 2H), 6.38 (dt, 1H), 6.67 (d, 1H), 6.83-6.93 (m, 3H), 6.97-7.20 (m,7H), 7.22-7.38 (m, 3H).

Example 26

(E)-(S)-2-Ethoxy-3-{4-[3-(3-phenoxy-phenyl)-allyloxy]-phenyl}-propionicacid

(E)-(S)-2-Ethoxy-3-{4-[3-(3-phenoxy-phenyl)-allyloxy]-phenyl}-propionicacid ethyl ester (example 25) (150 mg, 0.34 mmol) was dissolved inethanol (7 mL) and sodium hydroxide (1N, 4.4 mL, 4.4 mmol) added. Themixture was heated slightly to obtain a clear solution and then stirredat room temperature for 1.5 h. The ethanol was evaporated in vacuo andthe mixture acidified to pH 1 with 1N hydrochloric acid. The product wasisolated by extraction with ethyl acetate (40 mL×2). The combinedorganic phases were dried (MgSO₄), filtered and evaporated to give 130mg (91%) of the title compound as an oil.

¹H NMR (CDCl₃, 300 MHz) δ: 1.18 (t, 3H), 2.95 (dd, 1H), 3.08 (dd, 1H),3.38-3.50 (m, 1H), 3.55-3-65 (m, 1H), 4.05 (q, 1H), 4.65 (dd, 1H), 6.35(dt, 1H), 6.66 (d, 1H), 6.85-6.92 (m, 3H), 6.98-7.20 (m, 7H), 7.25-7.40(m, 3H).

Example 27

(S)-3-[4-(2-Benzofuran-3-yl-allyloxy)-phenyl]-2-ethoxy-propionic acidethyl ester

The title compound was prepared from benzo[b]furan-2-carboxaldehyde (9.8g, 0.07 mol) by a sequence analogous to that described in example 23.

¹H NMR (CDCl₃, 300 MHz) δ: 1.15 (t, 3H), 1.22 (t, 3H), 2.95 (d, 2H),3.30-3.42 (m, 1H), 3.55-3.65 (m, 1H), 3.98 (t, 1H), 4.15 (q, 2H), 4.73(d, 2H), 6.65-6.70 (m, 3H), 6.88 (d, 2H), 7.15 (d, 2H), 7.20-7-30 (m,2H), 7.45 (d, 1 H), 7.53 (d, 1 H).

Example 28

(S)-3-[4-(2-Benzofuran-3-yl-allyloxy)-phenyl]-2-ethoxy-propionic acid

The title compound was prepared from(S)-3-[4-(2-benzofuran-3-yl-allyloxy)-phenyl]-2-ethoxy-propionic acidethyl ester (example 27) (127 mg, 0.3 mmol) by a procedure analogous tothat described in example 26.

¹H NMR (CDCl₃, 300 MHz) δ: 1.15 (t, 3H), 3.30 (dd, 1H), 3.08 (dd, 1H),2.38-3.50 (m, 1H), 3.55-3.65 (m, 1H), 4.05 (q, 1H), 4.72 (d, 2H),6.55-6.68 (m, 3H), 6.90 (d, 1H), 7-13-7.30 (m, 5H), 7.42 (d, 1H), 7.50(d, 1H).

Example 29

(E)-(S)-3-{4-[3-(4-Benzyloxy-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionicacid ethyl ester

The title compound was prepared from 4-benzyloxybenzaldehyde (21.2 g,0.1 mol) by a sequence analogous to that described in example 23. Thetitle compound was purified on HPLC, using ethyl acetate/heptane (20:80)as eluent.

¹H NMR (CDCl₃, 300 MHz) δ: 1.15 (t, 3H), 1.22 (t, 3H), 2.95 (d, 2H),3.35 (m, 1H), 3.6 (m, 1H), 3.98 (t, 1H), 4.15 (q, 2H), 4.65 (dd, 2H),5.05 (s, 2H), 2.28 (dt, 1H), 6.65 (d, 1H), 6.85 (d, 2H), 6.93 (d, 2H),7.15 (d, 2H), 7.30-7.48 (m, 7H).

Example 30

(E)-(S)-3-{4-[3-(4-Benzyloxy-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionicacid

The title compound was prepared from(E)-(S)-3-{4-[3-(4-Benzyloxy-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionicacid ethyl ester (example 29) (80 mg, 0.17 mmol) by a procedureanalogous to that described in example 26.

¹H NMR (CDCl₃, 300 MHz): 1.18 (t, 3H), 2.95 (dd, 1H), 3.12 (dd, 1H),3.45-3.60 (m, 2H), 4.15 (dd, 1H), 4.65 (dd, 2H), 5.06 (s, 2H), 6.25 (dt,1 H), 6.65 (d, 1 H), 6.90 (d, 2H), 6.93 (d, 2H), 7.15 (d, 2H), 7.30-7.45(m, 7H).

Example 31

(E)-(S)-3-[4-(3-Benzo[1,3]dioxol-5-yl-allyloxy)-phenyl]-2-ethoxy-propionicacid ethyl ester

The title compound was prepared from piperonal (3.0 g, 20 mmol) by asequence analogous to that described in example 23. The title compoundwas purified on HPLC, using ethyl acetate/heptane (10:90) as eluent.

¹H NMR (CDCl₃, 300 MHz) δ: 1.15 (t, 3H), 1.22 (t, 3H), 2.96 (d, 2H),3.30-3.42 (m, 1H), 3.55-3.65 (m, 1H), 3.97 (t, 1H), 4.15 (q, 2H), 4.63(dd, 2H), 5.96 (s, 2H), 6.25 (dt, 1H), 6.63 (d, 1H), 6.75 (d, 1H),6.80-6.90 (m, 3H), 6.95 (d, 1H), 7.15 (d, 2H).

Example 32

(E)-(S)-3-[4-(3-Benzo[1,3]dioxol-5-yl-allyloxy)-phenyl]-2-ethoxy-propionicacid

The title compound was prepared from(E)-(S)-3-[4-(3-benzo[1,3]dioxol-5-yl-allyloxy)-phenyl]-2-ethoxy-propionicacid ethyl ester (example 31) (100 mg, 0.25 mmol) by a procedureanalogous to that described in example 26.

¹H NMR (CDCl₃, 300 MHz): 1.18 (t, 3H), 2.95 (dd, 1H), 3.08 (dd, 1H),3.38-3.50 (m, 1H), 3.55-3.68 (m, 1H), 4.05 (dd, 1H), 4.65 (dd, 2H), 5.95(s, 2H), 6.25 (dt, 1H), 6.63 (d, 1H), 6.75 (d, 1H), 6.83 (dd, 1H), 6.88(d, 2H), 6.95 (d, 1 H), 7.17 (d, 2H).

Example 33

(E)-(S)-3-{4-[3-(4-Allyloxy-phenyl)-allyloxy]-phenyl)-2-ethoxy-propionicacid ethyl ester

The title compound was prepared from 4-allyloxybenzaldehyde (3.24 g, 20mmol) by a sequence analogous to that described in example 23. The titlecompound was purified on HPLC, using ethyl acetate/heptane (10:90) aseluent.

¹H NMR (CDCl₃, 300 MHz) δ: 1.18 (t, 3H), 1.22 (t, 3H), 2.95 (d, 2H),3.30-3.42 (m, 1H), 3.55-3.68 (m, 1H), 3.98 (t, 1H), 4.17 (q, 2H), 4.53(d, 2H), 4.65 (dd, 2H), 5.29 (dd, 1H), 5.40 (dd, 1H), 5.97-6.13 (m, 1H),6.28 (dt, 1H), 6.65 (d, 1H), 6.88 (d, 4H), 7.15 (d, 2H), 7.35 (d, 2H).

Example 34

(E)-(S)-3-{4-[3-(4-Allyloxy-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionicacid

The title compound was prepared from(E)-(S)-3-{4-[3-(4-allyloxy-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionicacid ethyl ester (example 33) (40 mg, 0.1 mmol) by a procedure analogousto that described in example 26.

¹H NMR (CDCl₃, 300 MHz): 1.18 (t, 3H), 2.95 (dd, 1H), 3.10 (dd, 1H),3.39-3.50 (m, 1H), 3.53-3.65 (m, 1H), 4.05 (dd, 1H), 4.53 (d, 2H), 4.65(d, 2H), 5.29 (dd, 1H), 5.40 (dd, 1H), 5.98-6.14 (m, 1H), 6.28 (dt, 1H),6.65 (d, 1H), 6.85-6.95 (m, 4H), 7.15 (d, 2H), 7.35 (d, 2H).

Example 35

(E)-(S)-3-[4-(3-Benzofuran-7-yl-allyloxy)-phenyl]-2-ethoxy-propionicacid ethyl ester

The title compound was prepared from benzofuran-7-carboxaldehyde (1.46g, 10 mmol) by a sequence analogous to that described in example 23.

¹H NMR (CDCl₃, 300 MHz) δ: 1.15 (t, 3H), 1.22 (t, 3H), 2.95 (d, 2H),3.30-3.42 (m, 1H), 3.55-3.65 (m, 1H), 3.98 (t, 1H), 4.15 (q, 2H), 4.75(dd, 2H), 6,79 (d, 1H), 6.87-7.00 (m, 4H), 7.13-7.30 (m, 4H), 7.50 (dd,1H), 7.65 (d, 1H).

Example 36

(E)-(S)-3-[4-(3-Benzofuran-7-yl-allyloxy)-phenyl]-2-ethoxy-propionicacid

The title compound was prepared from(E)-(S)-3-[4-(3-benzofuran-7-yl-allyloxy)-phenyl]-2-ethoxy-propionicacid ethyl ester (example 35) (100 mg, 0.25 mmol) by a procedureanalogous to that described in example 26.

¹H NMR (CDCl^(3,) 300 MHz) δ: 1.15 (t, 3H), 2.95 (dd, 1H), 3.08 (dd,1H), 3.35-3.48 (m, 1H) 3.55-3.68 (m, 1H), 4.03 (dd, 1H), 4.75 (dd, 2H),6.78 (d, 1H), 6.90-7.00 (m, 4H), 7.13-7.32 (m, 4H), 7.50 (dd, 1H), 7.65(d, 1H), 10.1 (bs, 1H).

Example 37

(S)-3-[4-(3-Benzo[1,3]dioxol-4-yl-allyloxy)-phenyl]-2-ethoxy-propionicacid ethyl ester

The title compound was prepared from 2,3-methylenedioxybenzaldehyde (1.5g, 10 mmol) by a sequence analogous to that described in example 23.

¹H NMR (CDCl₃, 300 MHz) δ: 1.18 (t, 3H), 1.22 (t, 3H), 2.95 (d, 2H),3.30-3.42 (m, 1H), 3.55-3.65 (m, 1H), 3.97 (t, 1H), 4.15 (q, 2H), 4.65(d, 2H), 6.00 (s, 2H), 6.55-6.92 (m, 7H), 7.15 (d, 2H).

Example 38

(S)-3-[4-(3-Benzo[1,3]dioxol-4-yl-allyloxy)-phenyl]-2-ethoxy-propionicacid

The title compound was prepared from(S)-3-[4-(3-benzo[1,3]dioxol-4-yl-allyloxy)-phenyl]-2-ethoxy-propionicacid ethyl ester (example 37) (100 mg, 0.24 mmol) by a procedureanalogous to that described in example 26.

¹H NMR (CDCl₃, 300 MHz) δ: 1.17 (t, 3H), 2.95 (dd, 1H), 3.05 (dd, 1H),3.35-3.48 (m, 1H), 3.55-3.68 (m, 1H), 4.03 (dd, 1H), 4.65 (d, 2H), 6.00(s, 2H), 6.55-6.95 (m, 7H), 7.19 (d, 2H).

Example 39

(E)-(S)-2-Ethoxy-3-(4-[3-(9H-fluoren-2-yl)-allyloxy]-phenyl)-propionicacid ethyl ester

The title compound was prepared from fluorene-2-carboxaldehyde (9.7 g,50 mmol) by a sequence analogous to that described in example 23.

¹H NMR (CDCl₃, 300 MHz) δ: 1.18 (t, 3H), 1.22 (t, 3H), 2.97 (d, 2H),3.32-3.42 (m, 1H), 3.55-3.67 (m, 1H), 3.90 (s, 2H), 3.98 (t, 1H), 4.16(q, 2H), 4.70 (dd, 2H), 6.45 (dt, 1H), 6.80 (d, 1H), 6.90 (d, 2H), 7.1(d, 2H), 7.24-7.46 (m, 3H), 7.55 (d, 1H), 7.62 (s, 1H), 7.72-7.80 (m,2H).

Example 40

(E)-(S)-2-Ethoxy-3-(4-[3-(9H-fluoren-2-yl)-allyloxy]-phenyl)-propionicacid

The title compound was prepared from(E)-(S)-2-ethoxy-3-(4-[3-(9H-fluoren-2-yl)-allyloxy]-phenyl)-propionicacid ethyl ester (example 39) (275 mg, 0.6 mmol) by a procedureanalogous to that described in example 26.

¹H NMR (CDCl₃, 300 MHz) δ: 1.20 (t, 3H), 3.46 (dd, 1H), 3.12 (dd, 1H),3.43-3.65 (m, 2H), 3.90 (s, 2H), 4.05 (dd, 1H), 4.70 (dd, 2H), 6.46 (dt,1H), 6.80 (d, 1H), 6.92 (d, 2H), 7.17 (d, 2H), 7.23-7.46 (m, 3H), 7.53(d, 1H), 7.60 (s, 1H), 7.70-7.80 (m, 2H).

Example 41

(S)-2-Ethoxy-3-[4-(3-quinolin-2-yl-allyloxy)-phenyl]-propionic acidethyl ester

The title compound was prepared from 2-quinoline-carboxaldehyde (5.12 g,32.5 mmol) by a sequence analogous to that described in example 23.

¹H NMR (CDCl₃, 300 MHz) δ: 1.18 (t, 3H), 1.22 (t, 3H), 2.98 (d, 2H),3.32-3.42 (m, 1H), 3.55-3.66 (m, 1H), 3.98 (t, 1H), 4.17 (q, 2H), 4.80(d, 2H), 6.92 (d, 2H), 7.02 (m, 2H), 7.18 (d, 2H), 7.47-7.60 (m, 2H),7.70 (dt, 1H), 7.78 (d, 1H), 8.05 (d, 1H), 8.13 (d, 1H).

Example 42

(S)-2-Ethoxy-3-[4-(3-quinolin-2-yl-allyloxy)-phenyl]-propionic acid

(S)-2-Ethoxy-3-[4-(3-quinolin-2-yl-allyloxy)-phenyl]-propionic acidethyl ester (example 41) (150 mg, 0.37 mmol) was dissolved in ethanol (2mL) and sodium hydroxide (1N, 2.0 mL, 2.0 mmol) added. The mixture wasstirred at room temperature for 16 h. The reaction mixture wasconcentrated in vacuo, added 2-propanol (2 mL) and diethyl ether (2 mL).The title compound was isolated by filtration.

¹H NMR (CDCl₃/MeOD, 300 MHz) δ: 1.12 (t, 3H), 2.83 (dd, 1H), 3.02 (dd,1H), 3.32 (m, 1H), 3.56 (dd, 1H), 3.84 (dd, 1H), 4.85 (d, 2H), 6.90-7.10(m, 4H), 7.25 (m, 2H), 7.5-7.6 (m, 1H), 7.68-7.75 (m, 2H), 7.85 (d, 1H),8.03 (d, 1H), 8.23 (d, 1H).

Example 43

(E)-(S)-3-{4-[3-(3,5-Bis-benzyloxy-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionicacid ethyl ester

The title compound was prepared from 3,5-dibenzyloxybenzaldehyde (3.1 g,9.7 mmol) by a sequence analogous to that described in example 23.

¹H NMR (CDCl₃, 300 MHz) δ: 1.16 (t, 3H), 1.22 (t, 3H), 2.96 (d, 2H),3.30-3.42 (m, 1H), 3.54-3.65 (m, 1H), 3.98 (t, 1H), 4.17 (q, 2H), 4.65(d, 2H), 5.02 (s, 4H), 6.38 (dt, 1H), 6.55 (s, 1H), 6.58-6.70 (m, 3H),6.88 (d, 2H), 7.15 (d, 2H), 7.30-7.45 (m, 10H).

Example 44

(E)-(S)-3-{4-[3-(3,5-Bis-benzyloxy-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionicacid

The title compound was prepared from(E)-(S)-3-{4-[3-(3,5-bis-benzyloxy-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionicacid ethyl ester (example 43) (587 mg, 1.1 mmol) by a procedureanalogous to that described in example 26.

¹H NMR (CDCl₃, 300 MHz) δ: 1.15 (t, 3H), 2.95 (dd, 1H), 3.08 (dd, 1H),3.38-3.48 (m, 1H), 3.54-3.65 (m 1H), 4.03 (dd, 1H), 4.65 (d, 2H), 5.03(s, 4H), 6.35 (dt, 1H), 6.54 (t, 1H), 6.60-6.70 (m, 3H), 6.88 (d, 2H),7.16 (d, 2H), 7.30-7.45 (m, 10H).

Example 45

(E)-(S)-3-{4-[3-(3,5-Dimethoxy-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionicacid ethyl ester

The title compound was prepared from 3,5-dimethoxybenzaldehyde (5.5 g,33.1 mmol) by a sequence analogous to that described in example 23.

¹H NMR (CDCl₃, 300 MHz) δ: 1.18 (t, 3H), 1.22 (t, 3H), 2.95 (d, 2H),3.30-3.40 (m, 1H), 3.53-3.65 (m, 1H), 3.78 (s, 6H), 3.97 (t, 1H), 4.15(q, 2H), 4.65 (dd, 1H), 6.33-6.43 (m, 2H), 6.55 (d, 2H), 6.88 (d, 2H),7.15 (d, 2H).

Example 46

(E)-(S)-3-{4-[3-(3,5-Dimethoxy-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionicacid

The title compound was prepared from(E)-(S)-3-{4-[3-(3,5-dimethoxy-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionicacid ethyl ester (example 45) (300 mg, 0.7 mmol) by a procedureanalogous to that described in example 26.

¹H NMR (CDCl₃, 300 MHz) δ: 1.18 (t, 3H), 2.95 (dd, 1H), 3.07 (dd, 1H),3.37-3.48 (m, 1H), 3.55-3.67 (m, 1H), 3.80 (s, 6H), 4.05 (dd, 1H), 4.67(d, 2H), 6.33-6.45 (m, 1H), 6.55 (d, 2H), 6.65 (d, 1H), 6.88 (d, 2H),7.18 (d, 2H).

Example 47

(E)-(S)-2-Ethoxy-3-[4-(3-phenanthren-9-yl-allyloxy)-phenyl]-propionicacid ethyl ester

The title compound was prepared from phenanthrene-9-carboxaldehyde (4.1g, 20.0 mmol) by a sequence analogous to that described in example 23.

¹H NMR (CDCl₃, 300 MHz) δ: 1.16 (t, 3H), 1.22 (t, 3H), 2.95 (d, 2H),3.30-3.42 (m, 1H), 3.53-3.65 (m, 1H), 3.98 (t, 1H), 4.15 (q, 2H), 4.47(d, 2H), 6.47 (dt, 1H), 6.74 (d, 2H), 7.08 (d, 2H), 7.38 (d, 1H),7.53-7.70 (m, 4H), 7.82 (s, 1H), 7.85 (d, 1H), 8.15 (d, 1H), 8.65 (d,1H), 8.72 (d, 1H).

Example 48

(E)-(S)-2-Ethoxy-3-{4-[3-(2-methoxy-naphthalen-1-yl)-allyloxy]-phenyl}-propionicacid ethyl ester

The title compound was prepared from 2-methoxy-1-naphthaldehyde (4.1 g,22.1 mmol) by a sequence analogous to that described in example 23.

¹H NMR (CDCl₃, 300 MHz) δ: 1.16 (t, 3H), 1.22 (t, 3H), 2.97 (d, 2H),3.30-3.42 (m, 1H), 3.55-3.65 (m, 1H), 3.93 (s, 3H), 3.97 (t, 1H), 4.15(q, 2H), 4.85 (d, 2H), 6.48 (dt, 1H), 6.95 (d, 2H), 7.10-7.35 (m, 5H),7.45 (dt, 1H), 7.75-7.78 (m, 2H), 8.12 (d, 1H).

Example 49

(E)-(S)-2-Ethoxy-3-{4-[3-(2-methoxy-naphthalen-1-yl)-allyloxy]-phenyl}-propionicacid

The title compound was prepared from(E)-(S)-2-ethoxy-3-{4-[3-(2-methoxy-naphthalen-1-yl)-allyloxy]-phenyl}-propionicacid ethyl ester (example 48) (327 mg, 0.75 mmol) by a procedureanalogous to that described in example 26.

¹H NMR (CDCl₃, 300 MHz) δ: 1.16 (t, 3H), 2.95 (dd, 1H), 3.08 (dd, 1H),3.35-3.48 (m, 1H), 3.53-3.65 (m, 1H), 3.93 (s, 3H), 4.05 (dd, 1H), 4.82(dd, 2H), 6.49 (dt, 1H), 6.95 (d, 2H), 7.13 (d, 1H), 7.20 (d, 2H),7.23-7.35 (m, 2H), 7.44 (dt, 1H), 7.74 (d, 2H), 8.12 (d, 1H).

Example 50

(E)-(S)-Ethyl3-{4-[3-(4-Bromophenyl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate

a)

Sodium (5.52 g, 0.24 mol) was added to ethanol (250 ml) at 20° C. andthe mixture stirred until the metal had fully reacted. Triethylphosphonoacetate (62.72 g, 0.28 mol) was added, the mixture stirred for20 min, then a solution of 4-bromoacetophenone (39.81 g, 0.20 mol) inethanol (250 ml) was added and the reaction mixture heated to 80° C.under reflux for 17 h. The solution was cooled, the ethanol evaporatedand the resulting orange residue partitioned between 1N HCl (200 ml) andethyl acetate (200 ml). The aqueous layer was collected and furtherextracted with ethyl acetate (2×200 ml). The organic layers werecombined, washed with brine, dried (MgSO₄) and evaporated to an orangegum. This was purified by column chromatography on silica gel (3%diethyl ether in n-heptane eluent) to give the product, (E)-ethyl3-(4-bromophenyl)-but-2-enoate, as a colourless oil; 44.08 g (82%)

¹H NMR (300 MHz, CDCl₃) δ: 1.31 (3H, t), 2.54 (3H, s), 4.21 (2H, q),6.11 (1H, s), 7.34 (2H, dm), 7.48 (2H, dm). MS: 268/270 (M⁺), 240/242,239/241, 196/198, 116, 115 (100%). Microanalysis Calculated % C, 53.55;H, 4.87. Found % C, 53.86; H, 4.90.

b)

A 1M solution of DIBAL-H in toluene (42 ml, 42 mmol) was added dropwise,at −70° C. over 30 min, to a stirred solution of (E)-ethyl3-(4-bromophenyl)-but-2-enoate (4.55 g, 16.92 mmol) in dry THF (100 ml),and the mixture stirred for 1 h. Methanol (5 ml) was carefully added,followed by 1N HCl (300 ml) and the resulting mixture extracted withethyl acetate (3×200 ml). The combined organic extracts were washed withbrine, dried (Na₂SO₄), and evaporated to give the crude product as anoff-white solid, which was purified by recrystallisation from hot 1:4ether/n-heptane (250 ml) to give the product(E)-3-(4-bromophenyl)-but-2-en-1-ol as colourless needles: 3.10 g (81%)

Mpt. 58-59.5° C. ¹H NMR (300 MHz, CDCl₃) δ: 1.41 (1H, br s), 2.05 (3H,d), 4.36 (2H, d), 5.96 (1H, tq), 7.27 (2H, dm), 7.44 (2H, dm). MS:226/228 (M⁺), 211/213, 193/195, 183/185, 147 (100%), 132, 129, 115.Microanalysis Calculated % C, 52.89; H, 4.88; Br, 35.18. Found C, 53.24;H, 4.86; Br, 35.08.

c)

Azodicarboxylic dipiperidide (0.756 g, 3.0 mmol) was added at 0-5° C. toa stirred solution of tributylphosphine (0.74 ml, 0.61 g, 3.0 mmol),(S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.500 g, 2.10 mmol)and (E)-3-(4-bromophenyl)-but-2-en-1-ol (0.454 g, 2.0 mmol) in drybenzene (20 ml), the mixture warmed to room temperature, and stirred for2.5 days. The resulting mixture was diluted with water and ethyl acetate(50 ml each), the aqueous layer collected and further extracted withethyl acetate (50 ml). The organic layers were combined, washed withbrine, dried (MgSO₄) and evaporated. The crude product was then purifiedby column chromatography on silica gel (20% ethyl acetate in n-heptaneeluent) to give (E)-(S)-ethyl3-{4-[3-(4-bromophenyl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate as anoil; 0.780 g (87%).

¹H NMR (300 MHz, CDCl₃) δ: 1.17 (3H, t), 1.22 (3H, t), 2.10 (3H, s),2.96 (2H, d), 3.30-3.45 (1H, m), 3.55-3.70 (1H, m), 3.98 (1H, t), 4.17(2H, q), 4.70 (2H, d), 6.04 (1H, t), 6.86 (2H, m), 7.16 (2H, m), 7.29(2H, m), 7.44 (2H, m).

Example 51

(E)-(S)-3-{4-[3-(4-Bromophenyl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid

Sodium hydroxide (1M, 1.10 ml, 1.10 mmol) was added to a solution of(E)-(S)-ethyl3-{4-[3-(4-bromophenyl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate(example 50) (0.245 g, 0.548 mmol) in ethanol (10 ml) and the mixturestirred at room temperature for 18 h. The resulting mixture waspartitioned between water (50 ml) and ethyl acetate (50 ml) and theaqueous layer acidified to pH1 by addition of 1N HCl. The aqueous layerwas separated and further extracted with ethyl acetate (2×50 ml). Thecombined organic layers were washed with brine, dried (MgSO₄),evaporated and vacuum dried at 40° C. for 18 h, to give(E)-(S)-3-{4-[3-(4-bromophenyl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid as a colourless gum which contained 0.1 molar equivalents of ethylacetate; 0.22 g (96%).

¹H NMR (300 MHz, CDCl₃) δ: 1.18 (3H, t), 1.26 (ethyl acetate impurity,0.3H, t), 2.04 (ethyl acetate impurity, 0.2H, s), 2.11 (3H, s), 2.96(1H, dd), 3.08 (1H, dd), 3.40-3.55 (1H, m), 3.55-3-68 (1H, m), 4.06 (1H,dd), 4.15 (ethyl acetate impurity, 0.2H, q), 4.70 (2H, d), 6.04 (1H, t),6.88 (2H, m), 7.17 (2H, m), 7.29 (2H, m), 7.44 (2H, m), carboxylic acidproton not observed. LCMS: 441/443 (M+Na), 209/211 (100%).

Example 52

(E)-(S)-Ethyl3-{4-[3-(4′-Chloro-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate

a)

Tetrakis(triphenylphoshine)palladium(0) (0.26 g, 0.22 mmol, 4 mol %) wasadded, under nitrogen, to a stirred solution of (E)-ethyl3-(4-bromophenyl)-but-2-enoate (1.5 g, 5.57 mmol) {prepared as detailedin example 50 a} in DME (70 ml), and the resulting orange colouredsolution stirred at room temperature for 10 min. Aqueous 2M sodiumcarbonate (16.7 ml, 33.4 mmol) was then added, the mixture stirred for10 min, then 4-chlorophenyl boronic acid (1.3 g, 8.36 mmol) was added,and the reaction mixture heated to 80° C. for 18 h, under reflux. Thereaction mixture was diluted with 1N HCl (100 ml) and the productsextracted into ethyl acetate (2×100 ml). The combined organic extractswere washed with brine, dried (MgSO₄), and evaporated to give the crudeproduct, which was purified by column chromatography on silica gel (20%ethyl acetate in n-heptane eluent) to give the product,(E)-ethyl-3-(4′-chloro-biphenyl-4-yl)-but-2-enoate as a colourlesssolid; 1.17 g (70%).

¹H NMR (300 MHz, CDCl₃) δ: 1.33 (3H, t), 2.60 (3H, s), 4.23 (2H, q),6.20 (1H, s), 7.41 (2H, m), 7.52 (2H, m). MS: 300/302 (100%, M⁺),271/273, 255/257, 228/230, 165.

b)

A 1M solution of DIBAL-H in toluene (10 ml, 10 mmol) was added dropwise,at −70° C. over 10 min, to a stirred solution of(E)-ethyl-3-(4′-chloro-biphenyl-4-yl)-but-2-enoate (1.0 g, 3.32 mmol) indry THF (25 ml), and the mixture warmed to room temperature over 4 h.Methanol (1 ml) was carefully added, followed by 1N HCl (50 ml) and theresulting mixture extracted with ethyl acetate (2×50 ml). The combinedorganic extracts were washed with brine, dried (MgSO₄), and evaporatedto give the product, (E)-3-(4′-chloro-biphenyl-4-yl)-but-2-en-1-ol as acolourless solid: 0.86 g (100%).

Mpt. 137-142° C. ¹H NMR (300 MHz, CDCl₃) δ: 1.79 (1H, br s), 2.11 (3H,d), 4.40 (2H, d), 6.05 (1H, tq), 7.41 (2H, dm), 7.45-7.60 (6H, m).

c)

Azodicarboxylic dipiperidide (0.731 g, 2.9 mmol) was added at 0-5° C. toa stirred solution of tributylphosphine (0.71 ml, 0.58 g, 2.9 mmol),(S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.483 g, 2.03 mmol)and (E)-3-(4′-chloro-biphenyl-4-yl)-but-2-en-1-ol (0.500 g, 1.93 mmol)in dry benzene (15 ml), the mixture warmed to room temperature, andstirred for 3 h. The resulting mixture was diluted with water and ethylacetate (30 ml each), the aqueous layer collected and further extractedwith ethyl acetate (30 ml). The organic layers were combined, washedwith brine, dried (MgSO₄) and evaporated. The crude product was thenpurified by column chromatography on silica (20% ethyl acetate inn-heptane eluent) to give (E)-(S)-ethyl3-{4-[3-(4′-chloro-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionateas a gum; 0.69 g (75%).

¹H NMR (300 MHz, CDCl₃) δ: 1.17 (3H, t), 1.23 (3H, t), 2.16 (3H, s),2.96 (2H, d), 3.30-3.45 (1H, m), 3.55-3.68 (1H, m), 3.98 (1H, t), 4.17(2H, q), 4.74 (2H, d), 6.12 (1H, t), 6.88 (2H, m), 7.18 (2H, m), 7.40(2H, m), 7.45-7.60 (6H, m).

Example 53

(E)-(S)-3-{4-[3-(4′-Chloro-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid

Sodium hydroxide (1M, 2.3 ml, 2.3 mmol) was added to a solution of(E)-(S)-ethyl3-{4-[3-(4′-chloro-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate(example 52) (0.600 g, 1.25 mmol) in ethanol (10 ml) and the mixturestirred at room temperature for 18 h, then heated to 80° C. for 2 h. Theresulting mixture was partitioned between water (50 ml) and ethylacetate (50 ml) and the aqueous layer acidified to pH1 by addition of 1NHCl. The aqueous layer was separated and further extracted with ethylacetate (2×50 ml). The combined organic layers were washed with brine,dried (MgSO₄), evaporated, and the product and vacuum dried at 40° C.for 72 h, to give(E)-(S)-3-{4-[3-(4′-chloro-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid as a colourless solid; 0.53 g (94%).

¹H NMR (300 MHz, CDCl₃) δ: 1.18 (3H, t), 2.16 (3H, s), 2.97 (1H, dd),3.08 (1H, dd), 3.40-3.53 (1H, m), 3.55-3-68 (1H, m), 4.07 (1H, dd), 4.74(2H, d), 6.11 (1H, t), 6.90 (2H, m), 7.17 (2H, m), 7.39 (2H, m),7.45-7.60 (6H, m), carboxylic acid proton not observed.

Example 54

(E)-(S)-Ethyl2-Ethoxy-3-{4-[3-(5′-isopropyl-2′-methoxy-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionate

a)

Tetrakis(triphenylphoshine)palladium(0) (0.20 g, 0.18 mmol, 4 mol %) wasadded, under nitrogen, to a stirred solution of(E)-3-(4-bromophenyl)-but-2-en-1-ol (1.0 g, 4.40 mmol) {prepared asdetailed in example 50 b} in DME (55 ml), and the resulting orangecoloured solution stirred at room temperature for 10 min. Aqueous 2Msodium carbonate (13.2 ml, 26.4 mmol) was then added, the mixturestirred for 10 min, then 5-isopropyl-2-methoxyphenylboronic acid (1.28g, 6.60 mmol) was added, and the reaction mixture heated to 80° C. for18 h, under reflux. The reaction mixture was diluted with 1N HCl (100ml) and the products extracted into ethyl acetate (2×100 ml). Thecombined organic extracts were washed with brine, dried (MgSO₄), andevaporated to give the crude product, which was purified by columnchromatography on silica gel (1% methanol in dichloromethane eluent) togive the product,3-(5′-isopropyl-2′-methoxy-biphenyl-4-yl)-but-2-en-1-ol as a colourlessoil; 1.15 g (88%).

¹H NMR (300 MHz, CDCl₃) δ: 1.26 (6H, d), 1.33 (1H, br t), 2.12 (3H, s),2.91 (1H, septet), 3.80 (3H, s), 4.39 (2H, br t), 6.04 (1H, 7), 6.92(1H, d), 7.15-7.20 (2H, m), 7.42-7.55 (4H, m). MS: 296 (100%, M⁺), 281,263, 253.

b)

Azodicarboxylic dipiperidide (0.756 g, 3.0 mmol) was added at 0-5° C. toa stirred solution of tributylphosphine (0.74 ml, 0.61 g, 3.0 mmol),(S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.50 g, 2.10 mmol)and 3-(5′-isopropyl-2′-methoxy-biphenyl-4-yl)-but-2-en-1-ol (0.593 g,2.0 mmol) in dry benzene (15 ml), the mixture warmed to roomtemperature, and stirred for 4 h. The resulting mixture was diluted withwater (100 ml) and ethyl acetate (50 ml), the aqueous layer collectedand further extracted with ethyl acetate (50 ml). The organic layerswere combined, washed with brine, dried (MgSO₄) and evaporated. Thecrude product was then purified by column chromatography on silica (10%ethyl acetate in n-heptane eluent) to give (E)-(S)-ethyl2-ethoxy-3-{4-[3-(5′-isopropyl-2′-methoxy-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionateas a colourless oil; 0.67 g (65%).

¹H NMR (300 MHz, CDCl₃) δ: 1.17 (3H, t), 1.22 (3H, t), 1.26 (6H, d),2.16 (3H, s), 2.91 (1H, septet), 2.96 (2H, d), 3.30-3.45 (1H, m),3.54-3.66 (1H, m), 3.79 (3H, s), 3.98 (1H, t), 4.17 (2H, q), 4.74 (2H,d), 6.10 (1H, t), 6.84-6.95 (3H, m), 7.12-7.20 (4H, m), 7.42-7.57 (4H,m).

Example 55

(E)-(S)-2-Ethoxy-3-{4-[3-(5′-isopropyl-2′-methoxy-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionicacid

The title compound was prepared from (E)-(S)-ethyl2-ethoxy-3-{4-[3-(5′-isopropyl-2′-methoxy-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionate(example 54) (0.50 g, 0.968 mmol) and sodium hydroxide (1M, 1.93 ml,1.93 mmol) by a procedure analogous to that described in example 51,yielding(E)-(S)-2-ethoxy-3-{4-[3-(5′-isopropyl-2′-methoxy-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionicacid as a colourless gum, which contained 0.44 mol equivalents of ethylacetate; 0.48 g (94%).

¹H NMR (300 MHz, CDCl₃) δ: 1.18 (3H, t), 1.26 (6H, d), 1.26 (ethylacetate impurity, 1.32H, t), 2.04 (ethyl acetate impurity, 0.88H, s),2.16 (3H, s), 2.82-3.02 (2H, m), 3.08 (1H, dd), 3.40-3.52 (1H, m),3.52-3.68 (1H, m), 3.79 (3H, s), 4.06 (1H, dd), 4.15 (ethyl acetateimpurity, 0.88H, q), 4.75 (2H, d), 6.09 (1H, t), 6.88-6.95 (3H, m),7.12-7.20 (4H, m), 7.42-7.57 (4H, m), carboxylic acid proton notobserved.

Example 56

(E)-(S)-Ethyl2-Ethoxy-3-{4-[3-(5′-chloro-2′-methoxy-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionate

a)

(E)-Ethyl 3-(5′-chloro-2′-methoxy-biphenyl-4-yl)-but-2-enoate (1.07 g,91% yield) was prepared from 5-chloro-2-methoxyphenylboronic acid (1.0g, 5.36 mmol) and (E)-ethyl 3-(4-bromophenyl)-but-2-enoate (0.96 g, 3.57mmol) by a procedure analogous to that described in example 52 a.

¹H NMR (300 MHz, CDCl₃) δ: 1.33 (3H, t), 2.60 (3H, s), 3.81 (3H, s),4.23 (2H, q), 6.20 (1H, s), 6.91 (1H, d), 7.25-7.33 (2H, m), 7.47-7.57(4H, m). MS: 330/332 (100%, M⁺).

b)

(E)-Ethyl 3-(5′-chloro-2′-methoxy-biphenyl-4-yl)-but-2-enoate (0.90 g,2.72 mmol) was reduced with DIBAL-H by a procedure analogous to thatdescribed in example 52 b to give(E)-3-(5′-chloro-2′-methoxy-biphenyl-4-yl)-but-2-en-1-ol as a colourlessoil; 0.785 g (100%).

¹H NMR (300 MHz, CDCl₃) δ: 1.49 (1H, br s), 2.11 (3H, s), 3.80 (3H, s),4.39 (2H, d), 6.04 (1H, t), 6.90 (1H, d), 7.22-7.32 (2H, m), 7.47-7.57(4H, m). MS: 288/290 (100%, M⁺), 270/272, 2551257, 245/247.

c)

The title compound (0.54 g, 61% yield) was prepared from(E)-3-(5′-chloro-2′-methoxy-biphenyl-4-yl)-but-2-en-1-ol (0.50 g, 1.73mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.433 g,1.82 mmol) by a procedure analogous to that described in example 52 c.

¹H NMR (300 MHz, CDCl₃) δ: 1.17 (3H, t), 1.23 (3H, t), 2.16 (3H, s),2.96 (2H, d), 3.30-3.43 (1H, m), 3.55-3.65 (1H, m), 3.79 (3H, s), 3.98(1H, t), 4.17 (2H, q), 4.74 (2H, d), 6.10 (1H, t), 6.84-6.92 (3H, m),7.12-7.20 (2H, m), 7.22-7.32 (2H, m), 7.45-7.50 (4H, m). LCMS: 331/333(M+Na).

Example 57

(E)-(S)-3-{4-[3-(5′-Chloro-2′-methoxy-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid

The title compound was prepared from (E)-(S)-ethyl2-ethoxy-3-{4-[3-(5′-chloro-2′-methoxy-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionate(example 56) (0.47 g, 0.92 mmol) and sodium hydroxide (1M, 1.8 ml, 1.8mmol) by a procedure analogous to that described in example 51, yielding(E)-(S)-3-{4-[3-(5′-chloro-2′-methoxy-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid as a colourless gum, which contained 0.2 mol equivalents of ethylacetate; 0.43 g (98%).

¹H NMR (300 MHz, CDCl₃) δ: 1.19 (3H, t), 1.26 (ethyl acetate impurity,0.6H, t), 2.04 (ethyl acetate impurity, 0.4H, s), 2.16 (3H, s), 2.96(1H, dd), 3.10 (1H, dd), 3.42-3.52 (1H, m), 3.53-3.68 (1H, m), 3.80 (3H,s), 4.07 (1H, dd), 4.12 (ethyl acetate impurity, 0.4H), 4.74 (2H, d),6.10 (1H, t), 6.85-6.95 (3H, m), 7.12-7.20 (2H, m), 7.21-7.32 (2H, m),7.45-7.50 (4H, m), carboxylic acid proton not observed. LCMS: 503/505(M+Na).

Example 58

(E)-(S)-Ethyl3-{4-[3-(2′,3′-Dichloro-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate

a)

(E)-Ethyl 3-(2′,3′-Dichloro-biphenyl-4-yl)-but-2-enoate (1.07 g, 73%yield) was prepared from 2,3-dichlorophenylboronic acid (1.26 g, 6.60mmol) and (E)-ethyl 3-(4-bromophenyl)-but-2-enoate (1.0 g, 4.40 mmol) bya procedure analogous to that described in example 52 a.

Mpt. 64-66° C. ¹H NMR (300 MHz, CDCl₃) δ: 1.33 (3H, t), 2.62 (3H, d),4.23 (2H, q), 6.21 (1H, m), 7.20-7.30 (2H, m), 7.40-7.50 (3H, m),7.50-7.60 (2H, m). MS: 334/336/338 (100%, M⁺), 305/307/309, 289/291/293,262/264/266, 189/191.

b)

(E)-Ethyl 3-(2′,3′-dichloro-biphenyl-4-yl)-but-2-enoate (1.07 g, 3.19mmol) was reduced with DIBAL-H by a procedure analogous to thatdescribed in example 52 b to give(E)-3-(2′,3′-dichloro-biphenyl-4-yl)-but-2-en-1-ol as a colourlesssolid; 0.74 g (79%).

Mpt. 95-100° C. ¹H NMR (300 MHz, CDCl₃) δ: 1.45 (1H, br s), 2.13 (3H,s), 4.40 (2H, d), 6.07 (1H, t), 7.20-7.28 (2H, m), 7.35-7.42 (2H, m),7.42-7.53 (3H, m).

c)

The title compound (0.41 g, 80% yield) was prepared from(E)-3-(2′,3′-dichloro-biphenyl-4-yl)-but-2-en-1-ol (0.293 g, 1.0 mmol)and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.25 g, 1.05mmol) by a procedure analogous to that described in example 52 c.

¹H NMR (300 MHz, CDCl₃) δ: 1.17 (3H, t), 1.23 (3H, t), 2.18 (3H, s),2.96 (2H, d), 3.30-3.43 (1H, m), 3.55-3.65 (1H, m), 3.98 (1H, t), 4.17(2H, q), 4.75 (2H, d), 6.13 (1H, t), 6.84-6.92 (2H, m), 7.12-7.20 (2H,m), 7.21-7.32 (2H, m), 7.35-7.42 (2H, m), 7.43-7.53 (3H, m).

Example 59

(E)-(S)-3-{4-[3-(2′,3′-Dichloro-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid

The title compound was prepared from (E)-(S)-ethyl3-{4-[3-(2′,3′-dichloro-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate(example 58) (0.325 g, 0.63 mmol) and sodium hydroxide (1M, 1.27 ml,1.27 mmol) by a procedure analogous to that described in example 51,giving(E)-(S)-3-{4-[3-(2′,3′-dichloro-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid as a gum, which contained 0.28 mol equivalents of ethyl acetate;0.24 g (80%).

¹H NMR (300 MHz, CDCl₃) δ: 1.19 (3H, t), 1.26 (ethyl acetate impurity,0.84H, t), 2.05 (ethyl acetate impurity, 0.56H, s), 2.18 (3H, m), 2.98(1H, dd), 3.08 (1H, dd), 3.42-3.52 (1H, m), 3.53-3.68 (1H, m), 3.80 (3H,s), 4.07 (1H, dd), 4.12 (ethyl acetate impurity, 0.56H), 4.75 (2H, d),6.13 (1H, tm), 6.85-6.95 (2H, m), 7.14-7.20 (2H, m), 7.21-7.30 (2H, m),7.35-7.42 (2H, m), 7.42-7.53 (3H, m), carboxylic acid proton notobserved.

Example 60

(E)-(S)-Ethyl3-{4-[3-(2′,6′-Dimethoxy-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate

a)

(E)-Ethyl 3-(2′,6′-dimethoxy-biphenyl-4-yl)-but-2-enoate (1.02 g, 73%yield) was prepared from 2,6-dimethoxyphenylboronic acid (1.20 g, 6.60mmol) and (E)-ethyl 3-(4-bromophenyl)-but-2-enoate (1.0 g, 4.40 mmol) bya procedure analogous to that described in example 52 a.

Mpt. 120-123.5° C. ¹H NMR (300 MHz, CDCl₃) δ: 1.32 (3H, t), 2.62 (3H,d), 3.75 (6H, s), 4.23 (2H, q), 6.22 (1H, m), 6.67 (2H, d), 7.29 (1H,t), 7.38 (2H, dm), 7.53 (2H, dm). MS: 326 (100%, M⁺), 297, 281.

b)

(E)-Ethyl 3-(2′,6′-dimethoxy-biphenyl-4-yl)-but-2-enoate (0.90 g, 2.76mmol) was reduced with DIBAL-H by a procedure analogous to thatdescribed in example 52 b to give(E)-3-(2′,6′-dimethoxy-biphenyl-4-yl)-but-2-en-1-ol as a colourlesssolid; 0.82 g (100%).

Mpt. 70-75° C. ¹H NMR (300 MHz, CDCl₃) δ: 1.44 (1H, br s), 2.12 (3H, d),3.74 (6H, s), 4.38 (2H, d), 6.06 (1H, tm), 6.66 (2H, d), 7.13-7.37 (3H,m), 7.42-7.50 (2H, m). MS: 284 (100%, M⁺), 266, 251, 241.

c)

The title compound (0.41 g, 80% yield) was prepared from(E)-3-(2′,6′-dimethoxy-biphenyl-4-yl)-but-2-en-1-ol (0.50 g, 1.76 mmol)and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.44 g, 1.85mmol) by a procedure analogous to that described in example 52 c.

¹H NMR (300 MHz, CDCl₃) δ: 1.17 (3H, t), 1.22 (3H, t), 2.16 (3H, m),2.96 (2H, d), 3.30-3.43 (1H, m), 3.53-3.65 (1H, m), 3.73 (6H, s), 3.97(1H, t), 4.17 (2H, q), 4.75 (2H, d), 6.10 (1H, tm), 6.66 (2H, d),6.84-6.90 (2H, m), 7.13-7.20 (2H, m), 7.27 (1H, t), 7.30-7.38 (2H, m),7.45-7.52 (2H, m). LCMS: 527 (M+Na), 267 (100%).

Example 61

(E)-(S)-3-{4-[3-(2′,6′-Dimethoxy-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid

The title compound was prepared from (E)-(S)-ethyl3-{4-[3-(2′,6′-dimethoxy-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate(example 60) (0.565 g, 1.12 mmol) and sodium hydroxide (1M, 2.20 ml,2.20 mmol) by a procedure analogous to that described in example 51;giving(E)-(S)-3-{4-[3-(2′,6′-dimethoxy-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid as a gum; 0.49 g (92%).

¹H NMR (300 MHz, CDCl₃) δ: 1.18 (3H, t), 2.16 (3H, m), 2.98 (1H, dd),3.08 (1H, dd), 3.42-3.52 (1H, m), 3.53-3.68 (1H, m), 3.73 (6H, s), 4.07(1H, dd), 4.75 (2H, d), 6.10 (1H, tm), 6.66 (2H, d), 6.86-6.92 (2H, m),7.13-7.20 (2H, m), 7.27 (1H, t), 7.28-7.35 (2H, m), 7.45-7.50 (2H, m),carboxylic acid proton not observed. LCMS: 499 (M⁺), 267 (100%).

Example 62

(E)-(S)-Ethyl3-{4-[3-(4-Bromophenyl)-2-methyl-but-2-enyloxy]-phenyl}-2-ethoxy-propionate

a)

Sodium (1.37 g, 59.6 mmol) was added to ethanol (50 ml) at 20° C. andthe mixture stirred until the metal had fully reacted. Triethylphosphonoacetate (17.78 g, 74.62 mmol) was added, the mixture stirredfor 20 min, then a solution of 4-bromoacetophenone (9.90 g, 49.74 mmol)in ethanol (50 ml) was added and the reaction mixture heated to 80° C.under reflux for 17 h. The solution was cooled, the ethanol evaporatedand the residue partitioned between 1N HCl (100 ml) and ethyl acetate(100 ml). The aqueous layer was collected and further extracted withethyl acetate (2×200 ml). The organic layers were combined, washed withbrine, dried (MgSO₄) and evaporated to an orange gum. This was purifiedby column chromatography on silica gel (2% diethyl ether in n-heptaneeluent) to give the two double-bond isomer products as colourless oils.

(E)-Ethyl 3-(4-bromophenyl)-2-methyl-but-2-enoate; 5.38 g (38%).

¹H NMR (300 MHz, CDCl₃) δ: 1.34 (3H, t), 1.75 (3H, m), 2.22 (3H, m),4.26 (2H, q), 7.04 (2H, dm), 7.49 (2H, dm). MS: 282/284 (M⁺), 253/255,237/239, 208/210, 175, 157, 130, 129 (100%), 115.

And

(Z)-Ethyl 3-(4-bromophenyl)-2-methyl-but-2-enoate; 3.15 g (22%).

¹H NMR (300 MHz, CDCl₃) δ: 0.90 (3H, t), 2.01 (3H, s), 2.06 (3H, s),3.88 (2H, q), 7.00 (2H, dm), 7.41 (2H, dm). MS: 282/284 (M⁺), 253/255,237/239, 208/210, 157, 130, 129 (100%), 115.

b)

(E)-Ethyl 3-(4-bromophenyl)-2-methyl-but-2-enoate (2.83 g, 9.99 mmol)was reduced with DIBAL-H by a procedure analogous to that described inexample 52b to give (E)-3-(4-bromophenyl)-2-methyl-but-2-en-1-ol as acolourless oil; 1.82 g (75%).

¹H NMR (300 MHz, CDCl₃) δ: 1.60 (1H, br s), 1.66 (3H, m), 2.00 (3H, m),4.29 (2H, s), 7.01 (2H, dm), 7.44 (2H, dm). MS: 240/242 (M⁺),225/227,183/185 (100%), 161,146,143,128, 115.

c)

The title compound (0.83 g, 87% yield) was prepared from(E)-3-(4-bromophenyl)-2-methyl-but-2-en-1-ol (0.50 g, 2.07 mmol) and(S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.519 g, 2.18 mmol)by a procedure analogous to that described in example 52c.

¹H NMR (300 MHz, CDCl₃) δ: 1.18 (3H, t), 1.23 (3H, t), 1.68 (3H, m),2.04 (3H, m), 2.97 (2H, d), 3.30-3.43 (1H, m), 3.53-3.68 (1H, m), 3.98(1H, t), 4.18 (2H, q), 4.61 (2H, s), 6.88 (2H, dm), 7.04 (2H, dm), 7.17(2H, dm), 7.45 (2H, dm).

Example 63

(E)-(S)-3-{4-[3-(4-Bromophenyl)-2-methyl-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid

The title compound was prepared from (E)-(S)-ethyl3-{4-[3-(4-bromophenyl)-2-methyl-but-2-enyloxy]-phenyl}-2-ethoxy-propionate(example 62) (0.710 g, 1.54 mmol) and sodium hydroxide (1M, 3.10 ml,3.10 mmol) by a procedure analogous to that described in example 51;giving(E)-(S)-3-{4-[3-(4-bromophenyl)-2-methyl-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid as a colourless solid, which contained approximately 13 mol % ofethyl acetate impurity; 0.67 g (98%).

¹H NMR (300 MHz, CDCl₃) δ: 1.19 (3H, t), 1.68 (3H, m), 2.04 (3H, m),2.98 (1 H, dd), 3.08 (1H, dd), 3.42-3.54 (1H, m), 3.54-3.68 (1H, m),4.07 (1H, dd), 4.61 (2H, s), 6.90 (2H, dm), 7.04 (2H, dm), 7.17 (2H,dm), 7.45 (2H, dm), carboxylic acid proton not observed.

Example 64

(Z)-(S)-Ethyl3-{4-[3-(4-Bromophenyl)-2-methyl-but-2-enyloxy]-phenyl}-2-ethoxy-propionate

a)

(Z)-Ethyl 3-(4-bromophenyl)-2-methyl-but-2-enoate (1.42 g, 5.01 mmol),which was prepared as described in example 62 a, was reduced withDIBAL-H by a procedure analogous to that described in example 52 b togive (Z)-3-(4-bromophenyl)-2-methyl-but-2-en-1-ol as a colourless oil;1.19 g (98%).

¹H NMR (300 MHz, CDCl₃) δ: 1.38 (1H, br s), 1.89 (3H, s), 1.97 (3H, s),3.92 (2H, s), 7.01 (2H, dm), 7.42 (2H, dm). MS: 240/242 (M⁺), 225/227,183/185 (100%), 161, 146, 143, 128, 115.

c)

The title compound (0.91 g, 95% yield) was prepared from(Z)-3-(4-bromophenyl)-2-methyl-but-2-en-1-ol (0.50 g, 2.07 mmol) and(S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.519 g, 2.18 mmol)by a procedure analogous to that described in example 52 c.

¹H NMR (300 MHz, CDCl₃) δ: 1.16 (3H, t), 1.21 (3H, t), 1.93 (3H, s),2.02 (3H, s), 2.93 (2H, d), 3.28-3.42 (1H, m), 3.53-3.68 (1H, m), 3.95(1H, t), 4.16 (2H, q), 4.25 (2H, s), 6.69 (2H, dm), 7.04 (2H, dm), 7.09(2H, dm), 7.41 (2H, dm).

Example 65

(Z)-(S)-3-{4-[3-(4-Bromophenyl)-2-methyl-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid

The title compound was prepared from (Z)-(S)-ethyl3-{4-[3-(4-bromophenyl)-2-methyl-but-2-enyloxy]-phenyl}-2-ethoxy-propionate(example 64) (0.82 g, 1.78 mmol) and sodium hydroxide (1M, 3.60 ml, 3.60mmol) by a procedure analogous to that described in example 51; giving(Z)-(S)-3-{4-[3-(4-bromophenyl)-2-methyl-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid as a colourless solid, which contained approximately 15 mol % ofethyl acetate impurity; 0.766 g (100%).

¹H NMR (300 MHz, CDCl₃) δ: 1.17 (3H, t), 1.93 (3H, s), 2.02 (3H, s),2.93 (1H, dd), 3.04 (1H, dd), 3.40-3.52 (1H, m), 3.52-3.65 (1H, m), 4.03(1H, dd), 4.26 (2H, s), 6.71 (2H, dm), 7.04 (2H, dm), 7.09 (2H, dm),7.41 (2H, dm), carboxylic acid proton not observed.

Example 66

(E)-(S)-Ethyl2-Ethoxy-3-[4-(3-[1,1′;3′,1″]terphenyl-4″-yl-but-2-enyloxy)-phenyl]-propionate

a)

(E)-Ethyl 3-[1,1′;3′,1″]terphenyl-4″-yl-but-2-enoate (1.02 g, 68% yield)was prepared from 3-biphenylboronic acid (1.31 g, 6.60 mmol) and(E)-ethyl 3-(4-bromophenyl)-but-2-enoate (1.0 g, 4.40 mmol) by aprocedure analogous to that described in example 52 a.

¹H NMR (300 MHz, CDCl₃) δ: 1.33 (3H, t), 2.62 (3H, d), 4.23 (2H, q),6.21 (1H, s), 7.30-7.70 (12H, m), 7.82 (1H, m). LCMS: 343 (100%, M⁺),297.

b)

(E)-Ethyl 3-[1,1′;3′,1″]terphenyl-4″-yl-but-2-enoate (0.95 g, 2.77 mmol)was reduced with DIBAL-H by a procedure analogous to that described inexample 52 b to give (E)-3-[1,1′;3′,1″]terphenyl-4″-yl-but-2-en-1-ol asa colourless solid; 0.81 g (97%).

¹H NMR (300 MHz, CDCl₃) δ: 1.37 (1H, br s), 2.13 (3H, s), 4.40 (2H, d),6.06 (1H, tm), 7.30-7.70 (12H, m), 7.81 (1H, m). LCMS: 283 (100%,M+H-H₂O). Microanalysis Calculated % C, 87.96; H, 6.71. Found % C,87.85; H, 6.74.

c)

The title compound (0.41 g, 80% yield) was prepared from(E)-3-[1,1′;3′,1″]terphenyl-4″-yl-but-2-en-1-ol (0.30 g, 1.0 mmol) and(S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.25 g, 1.05 mmol) bya procedure analogous to that described in example 52 c.

¹H NMR (300 MHz, CDCl₃) δ: 1.17 (3H, t), 1.22 (3H, t), 2.18 (3H, s),2.96 (2H, d), 3.30-3.43 (1H, m), 3.55-3.68 (1H, m), 3.98 (1H, t), 4.17(2H, q), 4.75 (2H, d), 6.13 (1H, t), 6.89 (2H, dm), 7.17 (2H, dm),7.30-7.70 (12H, m), 7.81 (1H, m). Microanalysis Calculated % C, 80.74;H, 6.97. Found % C, 80.84; H, 7.28.

Example 67

(E)-(S)-2-Ethoxy-3-[4-(3-[1,1′;3′,1″]terphenyl-4″-yl-but-2-enyloxy)-phenyl]-propionicacid

The title compound was prepared from (E)-(S)-ethyl2-ethoxy-3-[4-(3-[1,1′;3′,1″]terphenyl-4″-yl-but-2-enyloxy)-phenyl]-propionate(example 66) (0.185 g, 0.36 mmol) and sodium hydroxide (1M, 0.71 ml,0.71 mmol) by a procedure analogous to that described in example 51;giving(E)-(S)-2-ethoxy-3-[4-(3-[1,1′;3′,1″]terphenyl-4″-yl-but-2-enyloxy)-phenyl]-propionicacid as a gum; 0.145 g (83%).

¹H NMR (300 MHz, CDCl₃) δ: 1.19 (3H, t), 2.18 (3H, m), 2.99 (1H, dd),3.09 (1H, dd), 3.40-3.53 (1H, m), 3.53-3.68 (1H, m), 4.07 (1H, dd), 4.75(2H, d), 6.13 (1H, tm), 6.90 (2H, dm), 7.17 (2H, dm), 7.30-7.70 (12H,m), 7.81 (1H, m), carboxylic acid proton not observed.

Example 68

(E)-(S)-Ethyl2-Ethoxy-3-{4-[3-(3′-methyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionate

a)

(E)-3-(3′-Methyl-biphenyl-4-yl)-but-2-enoate (0.795 g, 65% yield) wasprepared from 3-tolylboronic acid (0.90 g, 6.60 mmol) and (E)-ethyl3-(4-bromophenyl)-but-2-enoate (1.0 g, 4.40 mmol) by a procedureanalogous to that described in example 52 a.

¹H NMR (300 MHz, CDCl₃) δ: 1.33 (3H, t), 2.43 (3H, s), 2.61 (3H, s),4.23 (2H, q), 6.20 (1H, s), 7.18 (1H, dm), 7.34 (1H, tm), 7.41 (2H, dm),7.52-7.63 (4H, m). LCMS: 281 (M+H), 235 (100%).

b)

(E)-3-(3′-Methyl-biphenyl-4-yl)-but-2-enoate (0.74 g, 2.64 mmol) wasreduced with DIBAL-H by a procedure analogous to that described inexample 52 b to give (E)-3-(3′-methyl-biphenyl-4-yl)-but-2-en-1-ol as acolourless solid; 0.63 g (85%).

¹H NMR (300 MHz, CDCl₃) δ: 1.36 (1 H, br s), 2.12 (3H, s), 2.42 (3H, s),4.39 (2H, d), 6.05 (1H, tm), 7.16 (1H, dm), 7.33 (1H, tm), 7.40 (2H,dm), 7.48 (2H, dm), 7.56 (2H, dm). LCMS: 221 (100%, M+H-H₂O).

c)

The title compound (0.365 g, 78% yield) was prepared from(E)-3-(3′-methyl-biphenyl-4-yl)-but-2-en-1-ol (0.238 g, 1.0 mmol) and(S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.25 g, 1.05 mmol) bya procedure analogous to that described in example 52 c.

¹H NMR (300 MHz, CDCl₃) δ: 1.17 (3H, t), 1.22 (3H, t), 2.17 (3H, s),2.42 (3H, s), 2.96 (2H, d), 3.30-3.43 (1H, m), 3.55-3.68 (1H, m), 3.98(1H, t), 4.17 (2H, q), 4.74 (2H, d), 6.11 (1H, t), 6.90 (2H, dm),7.13-7.23 (3H, m), 7.33 (1H, t), 7.36-7.44 (2H, m), 7.45-7.60 (4H, m).Microanalysis Calculated % C, 78.57; H, 7.47. Found % C, 78.90; H, 7.70.

Example 69

(E)-(S)-2-Ethoxy-3-{4-[3-(3′-methyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionicacid

The title compound was prepared from(E)-(S)-2-ethoxy-3-{4-[3-(3′-methyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionate(example 68) (0.225 g, 0.49 mmol) and sodium hydroxide (1M, 0.98 ml,0.98 mmol) by a procedure analogous to that described in example 51;giving(E)-(S)-ethoxy-3-{4-[3-(3′-methyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionicacid as a gum; 0.20 g (95%).

¹H NMR (300 MHz, CDCl₃) δ: 1.18 (3H, t), 2.17 (3H, m), 2.42 (3H, s),2.97 (1H, dd), 3.09 (1H, dd), 3.42-3.54 (1H, m), 3.55-3.68 (1H, m), 4.07(1H, dd), 4.75 (2H, d), 6.11 (1H, tm), 6.90 (2H, dm), 7.10-7.23 (3H, m),7.35 (1H, t), 7.37-7.44 (2H, m), 7.45-7.60 (4H, m), carboxylic acidproton not observed.

Example 70

(E)-(S)-Ethyl3-{4-[3-(3′-Acetyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate

a)

3-Acetylphenylboronic acid (7.10 g, 43.3 mmol) was coupled with(E)-3-(4-bromophenyl)-but-2-en-1-ol (5.76 g, 25.0 mmol) by a procedureanalogous to that described in example 54 a to give(E)-3-(3′-acetyl-biphenyl-4-yl)-but-2-en-1-ol as an off-white solid;5.33 g (79%). This solid was recrystallised from aqueous ethanol to givea first crop of very pure (E)-3-(3′-acetyl-biphenyl-4-yl)-but-2-en-1-olas colourless platelets; 2.78 g (41%) and a second crop of(E)-3-(3′-acetyl-biphenyl-4-yl)-but-2-en-1-ol as an amorphous off-whitesolid; 2.53 g (37%).

Mpt. 85-86° C. ¹H NMR (300 MHz, CDCl₃) δ: 1.46 (1H, br t), 2.13 (3H, d),2.66 (3H, s), 4.41 (2H, br t), 6.07 (1H, tm), 7.50-7.62 (5H, m), 7.80(1H, dm), 7.92 (1H, dm), 8.19 (1H, m). MS: 266 (M⁺), 251, (M-Me), 248(M−H₂O), 223 (100%). Microanalysis Calculated % C, 81.17; H, 6.81. Found% C, 81.22; H, 6.83.

b)

The title compound (0.16 g, 65% yield) was prepared from(E)-3-(3′-acetyl-biphenyl-4-yl)-but-2-en-1-ol (0.133 g, 0.50 mmol) and(S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.125 g, 0.525 mmol)by a procedure analogous to that described in example 52 c.

¹H NMR (300 MHz, CDCl₃) δ: 1.17 (3H, t), 1.23 (3H, t), 2.18 (3H, s),2.66 (3H, s), 2.92 (2H, d), 3.30-3.43 (1H, m), 3.55-3.68 (1H, m), 3.98(1H, t), 4.17 (2H, q), 4.75 (2H, d), 6.13 (1H, t), 6.89 (2H, dm), 7.17(2H, dm), 7.50-7.64 (5H, m), 7.80 (1H, dm), 7.92 (1H, dm), 8.19 (1H, m).

Example 71

(E)-(S)-2-Ethoxy-3-{4-[3-(5′-isopropyl-2′-methoxy-biphenyl-4-yl)-allyloxy]-phenyl}-propionicacid ethyl ester

a)

(E)-3-(4-Bromo-phenyl)-acrylic acid ethyl ester was prepared from4-bromobenzaldehyde (20.0 g, 0.11 mol) by a procedure analogous to thatdescribed in example 23 a.

b)

(E)-3-(4-Bromo-phenyl)-acrylic acid ethyl ester (450 mg, 2.0 mmol) wasreacted with 5-isopropyl-2-methoxy-benzene boronic acid (776 mg, 4.0mmol) by a procedure described in example 52 a, to give(E)-3-(5′-Isopropyl-2′-methoxy-biphenyl-4-yl)-acrylic acid ethyl ester.

c)

(E)-3-(5′-Isopropyl-2′-methoxy-biphenyl-4-yl)-acrylic acid ethyl esterwas reduced by DIBAL-H by a procedure analogous to that described inexample 52 b to give(E)-3-(5′-isopropyl-2′-methoxy-biphenyl-4-yl)-prop-2-en-1-ol.

d)

The title compound was prepared from(E)-3-(5′-isopropyl-2′-methoxy-biphenyl-4-yl)-prop-2-en-1-ol by aprocedure analogous to that described in 52 c.

¹H NMR (300 MHz, CDCl₃) δ: 1.13-1.30 (m, 12H), 2.85-3.0 (m, 3H),3.30-3.42 (m, 1H), 3.53-3.67 (m, 1H), 2.78 (s, 3H), 3.98 (t, 1H), 4.15(q, 2H), 4.70 (dd, 2H), 6.43 (dt, 1H), 6.75 (d, 1H), 6.85-6.95 (m, 3H),7.15 (d, 4H), 7.44 (d, 2H), 7.52 (d, 2H).

Example 72

(E)-(S)-2-Ethoxy-3-{4-[3-(5′-isopropyl-2′-methoxy-biphenyl-4-yl)-allyloxy]-phenyl}-propionicacid

The title compound was prepared from(E)-(S)-2-ethoxy-3-{4-[3-(5′-isopropyl-2′-methoxy-biphenyl-4-yl)-allyloxy]-phenyl}-propionicacid ethyl ester (example 71) (370 mg, 0.78 mmol) by a procedureanalogous to that described in example 26.

¹H NMR (CDCl₃, 300 MHz) δ: 1.18 (t, 3H), 1.26 (d, 6H), 2.85-3.03 (m,2H), 3.08 (dd, 1H), 3.35-3.48 (m, 1H), 3.55-3.68 (m, 1H), 3.75 (s, 3H),4.03 (dd, 1H), 4.67 (d, 2H), 6.43 (dt, 1H), 6.75 (d. 1H), 6.87-6.95 (m,3H), 7.13-7.23 (m, 4H), 7.43 (d, 2H), 7.53 (d, 2H).

Example 73

(E)-(S)-3-{4-[3-(3,5-Distyryl-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionicacid ethyl ester

a)

Bu₄NBr (2.0 g, 6.3 mmol), K₂CO₃ (7.8 g, 56.7 mmol), Pd(Oac)₂ (250 mg,1.1 mmol) and styrene (20 mL, 175 mmol) were stirred for 5 min undernitrogen. To the mixture was added 3,5-dibromobenzaldehyde (5.0 g, 18.9mmol) in dry DMF (5.0 mL), and the mixture was stirred at 65° C. for 16h. The reaction mixture was diluted with ethyl acetate (20 mL) and thesolution filtered. The filtrate was diluted with water and extractedwith ethyl acetate (3×50 mL). The organic layers were combined, driedover MgSO₄, and concentrated under vacuum. To the residue was added amixture of toluene/petroleum ether (1:1) (50 mL) and3,5-distyryl-benzaldehyde (4.95 g, 85%) was isolated by filtration.

b)

The title compound was prepared from 3,5-distyryl-benzaldehyde (3.8 g,10.0 mmol) by a sequence analogous to that described in example 23b-c.

¹H NMR (CDCl₃, 300 MHz) δ: 1.15 (t, 3H), 1.22 (t, 3H), 2.98 (d, 2H),3.32-3.42 (m, 1H), 3.55-3.68 (m, 1H), 3.98 (t, 1H), 4.12 (t, 1H), 4.18(q, 2H), 4.72 (dd, 2H), 6.50 (dt, 1H), 6.78 (d, 1H), 6.90 (d, 1H),7.08-7.32 (m, 8H), 7.39 (t, 4H), 7.45 (s, 2H), 7.53 (d, 5H).

Example 74

(E)-(S)-3-{4-[3-(3,5-Distyryl-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionicacid

(E)-(S)-3-{4-[3-(3,5-Distyryl-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionicacid ethyl ester (example 73) (335 mg, 0.6 mmol) was dissolved in warmethanol (20 mL) and sodium hydroxide (1N, 0.9 mL, 0.9 mmol) added. Themixture was stirred at room temperature for 16 h. The title compound asa sodium salt was isolated by filtration and washed with ethanol/water(10:1), yielding 190 mg (57%).

¹H NMR (CDCl₃, 300 MHz) δ: 0.98 (t, 3H), 2.63 (dd, 1H), 2.85 (dd, 1H),3.05-3.15 (m, 1H), 3.50-3.64 (m, 2H), 4.75 (d, 2H), 6.68 (dt, 1H), 6.80(d, 1H), 6.90 (d, 2H), 7.15 (d, 2H), 7.25-7.48 (m, 10H), 7.60-7.70 (m,6H), 7.75 (s, 1H).

Example 75

(E)-(S)-3-{4-[3-(3,5-Diisopropoxy-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionicacid ethyl ester

a)

To a solution of 3,5-dihydroxybenzaldehyde (3.0 g, 22.0 mmol) in DMF (17mL) was added potassium carbonate (12.1 g, 87.0 mmol) and 2-bromopropane(28.5 g, 232 mmol). The reaction mixture was heated at 100° C. for 3 h.The mixture was filtered and washed with ethyl acetate. The filtrate wasadded water and the organic phase isolated. The aqueous phase wasextracted once more with ethyl acetated. The combined organic phaseswere dried (MgSO₄), filtered and concentrated in vacuo. The residue waspurified by flash chromatography eluting with toluene to give 3.8 g(79%) of 3,5-diisopropoxy-benzaldehyde as a yellow oil.

¹H NMR (CDCl₃, 300 MHz) δ: 1.35 (d, 12H), 4.60 (heptet, 2H), 6.68 (t,1H), 6.97 (d, 2H).

b)

The title compound was prepared from 3,5-diisopropoxy-benzaldehyde by asequence analogous to that described in example 23.

¹H NMR (CDCl₃, 300 MHz) δ: 1.15 (t, 3H), 1.22 (t, 3H), 1.32 (d, 12H),2.96 (d, 2H), 3.32-3.42 (m, 1H), 3.55-3.65 (m, 1H), 3.98 (t, 1H), 4.16(q, 2H), 4.53 (heptet, 2H), 4.65 (dd, 2H), 6.30-6.40 (m, 2H), 6.52 (d,2H), 6.62 (d, 1H), 6.88 (d, 2H), 7.15 (d, 2H).

Example 76

(E)-(S)-3-{4-[3-(3,5-Diisopropoxy-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionicacid

The title compound was prepared from(E)-(S)-3-{4-[3-(3,5-diisopropoxy-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionicacid ethyl ester (example 75) (800 mg, 1.7 mmol) by a procedureanalogous to that described in example 26.

¹H NMR (CDCl₃, 300 MHz) δ: 1.18 (t, 3H), 1.32 (d, 12H), 2.95 (dd, 1H),3.10 (dd, 1H), 3.40-3.52 (m, 1H), 3.55-3.65 (m, 1H), 4.05 (dd, 1H), 4.53(heptet, 2H), 6.30-6.40 (m, 2H), 6.52 (d, 2H), 6.62 (d, 1H), 6.88 (d,2H), 7.15 (d, 2H).

Example 77

(S)-3-{4-[3-(3-Bromo-5-styryl-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionicacid ethyl ester

a)

A mixture of styrene (2.0 g, 18.9 mmol), potassium carbonate (7.8 g,56.7 mmol), tetra-N-butylammonium bromide (2.0 g, 6.3 mmol) andpalladium(II) acetate (250 mg, 1.11 mmol), under nitrogen, was stirredfor 10 min. A solution of 3,5-dibromobenzaldehyde (5.0 g, 18.9 mmol) indry DMF (10 mL) was added and the mixture heated at 65° C. for 16 h. Thereaction mixture was concentrated in vacuo, and the product purified byflash chromatography (heptane/ethyl acetate 1:4) to give 1.7 g of3-bromo-5-styryl-benzaldehyde.

b)

The title compound was prepared from 3-bromo-5-styryl-benzaldehyde by asequence analogous to that described in example 23.

¹H NMR (CDCl₃, 300 MHz) δ: 1.18 (t, 3H), 1.23 (t, 3H), 2.96 (d, 2H),3.30-3.42 (m, 1H), 3.55-3.65 (m, 1H), 3.98 (t, 1H), 4.15 (q, 2H), 4.68(d, 2H), 6.43 (dt, 1H), 6.66 (d, 1H), 6.88 (d, 2H), 6.93-7.56 (m, 12H).

Example 78

(S)-3-{4-[3-(3-Bromo-5-styryl-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionicacid

The title compound was prepared from(S)-3-{4-[3-(3-bromo-5-styryl-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionicacid ethyl ester (example 77) (800 mg, 1.7 mmol) by a procedureanalogous to that described in example 26.

¹H NMR (CDCl₃, 300 MHz) δ: 1.18 (t, 3H), 2.98 (dd, 1H), 3.10 (dd, 1H),3.40-3.53 (m, 1H), 3.54-3.68 (m, 1H), 4.05 (dd, 1H), 4.68 (dd, 2H), 6.43(dt, 1H), 6.68 (s, 1H), 6.88 (d, 2H), 6.94-7.56 (m, 12H).

Example 79

(E)-(S)-2-Ethoxy-3-[4-(3-phenyl-allyloxy)-phenyl]-propionic acid ethylester

The title compound was prepared from 3-phenyl-prop-2-en-1-ol (270 mg,2.0 mmol) by a sequence analogous to that described in example 23c.

¹H NMR (CDCl₃, 300 MHz) δ: 1.18 (t, 3H), 1.22 (t, 3H), 2.95 (d, 2H),3.30-3.42 (m, 1H), 3.53-3.65 (m, 1H), 3.98 (t, 1H), 4.15 (q, 2H), 4.68(dd, 2H), 6.41 (dt, 1H), 6.73 (dt, 1H), 6.88 (d, 2H), 7.15 (d, 2H),7.21-7.38 (m, 3H), 7.38-7.43 (m, 2H).

Example 80

(E)-(S)-2-Ethoxy-3-[4-(3-phenyl-allyloxy)-phenyl]-propionic acid

The title compound was prepared from(E)-(S)-2-ethoxy-3-[4-(3-phenyl-allyloxy)-phenyl]-propionic acid ethylester (example 79) (700 mg, 2.0 mmol) by a procedure analogous to thatdescribed in example 26.

¹H NMR (CDCl₃, 300 MHz) δ: 1.18 (t, 3H), 2.95 (dd, 1H), 3.10 (dd, 1H),4.42-3.53 (m, 1H), 3.53-3.64 (m, 1H), 4.05 (dd, 1H), 4.68 (dd, 2H), 6.42(dt, 1H), 6.72 (d, 1H), 6.89 (d, 2H), 7.15 (d, 1H), 7.22-7.37 (m, 3H),7.40 (d, 2H).

Example 81

(E)-(S)-3-{4-[3-(2′,3′-Dichloro-biphenyl-4-yl)-allyloxy]-phenyl}-2-ethoxy-propionicacid ethyl ester

a)

(E)-3-(4-Bromo-phenyl)-acrylic acid ethyl ester was prepared from3-bromobenzaldehyde (20.0 g, 0.11 mol) by a sequence analogous to thatdescribed in example 23a.

b)

The title compound was prepared from (E)-3-(4-bromo-phenyl)-acrylic acidethyl ester and 2,3-dichlorobenzene boronic acid by a sequence analogousto that described in example 52a-c.

¹H NMR (CDCl₃, 300 MHz) δ: 1.18 (t, 3H), 1.23 (t, 3H), 2.95 (d, 2H),3.30-3.42 (m, 1H), 3.53-3.65 (m, 1H), 3.98 (t, 1H), 4.15 (q, 2H), 4.70(dd, 2H), 6.47 (dt, 1H), 6.7 (d, 1H), 6.88 (d, 2H), 7.15 (d, 2H),7.20-7.28 (m, 2H), 7.35 (d, 2H), 7.43-7.52 (m, 3H).

Example 82

(E)-(S)-3-{4-[3-(2′,3′-Dichloro-biphenyl-4-yl)-allyloxy]-phenyl}-2-ethoxy-propionicacid

The title compound was prepared from(E)-(S)-3-{4-[3-(2′,3′-dichloro-biphenyl-4-yl)-allyloxy]-phenyl}-2-ethoxy-propionicacid ethyl ester (example 81) by a procedure analogous to that describedin example 26.

¹H NMR (MeOD, 300 MHz) δ: 1.12 (t, 3H), 2.88 (dd, 1H), 3.0 (dd, 1H),3.30-3.42 (m, ₁H), 3.3-3.65 (m, 1H), 4.0 (dd, 1H), 4.70 (dd, 2H), 6.52(dt, 1H), 6.80 (d, 1H), 6.90 (d, 2H), 7.18 (d, 2H), 7.25-7.40 (m, 4H),7.48-7.55 (m, 3H).

Example 83

(E)-(S)-3-{4-[3-(3,5-Bis-phenylethynyl-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionicacid ethyl ester

a)

A mixture of potassium carbonate (2.1 g, 15.2 mmol),tetra-N-butylammonium bromide (0.75 g, 2.4 mmol) and palladium(II)acetate (75 mg, 0.33 mmol) in dry DMF (8 ML), under nitrogen, wasstirred for 10 min. 3-(3,5-Dibromophenyl)-acrylic acid ethyl ester (1.2g, 3.6 mmol) was added and the mixture cooled on ice. Phenylacetylene(4.0 mL, 36.0 mmol) was added and the mixture stirred at roomtemperature for 7 days. The reaction mixture was added water and theproduct extracted with ethyl acetate (×3). The combined organic phaseswere dried and concentrated in vacuo to give crude3-(3,5-bis-phenylethynyl-phenyl)-acrylic acid ethyl ester.

b)

The title compound was prepared from3-(3,5-bis-phenylethynyl-phenyl)-acrylic acid ethyl ester by a sequenceanalogous to that described in example 23b-c.

¹H NMR (CDCl₃, 300 MHz) δ: 1.18 (t, 3H), 1.23 (t, 3H), 2.96 (d, 2H),3.30-3.42 (m, 1H), 3.55-3.67 (m, 1H), 3.98 (t, 1H), 4.15 (q, 2H), 4.70(d, 2H), 6.46 (dt, 1H), 6.68 (d, 1H), 6.88 (d, 2H), 7.15 (d, 2H),7.30-7.38 (m, 6H), 7.48-7.58 (m, 6H), 7.60 (s, 1H).

Example 84

(E)-(S)-3-{4-[3-(3,5-Bis-phenylethynyl-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionicacid

The title compound was prepared from(E)-(S)-3-{4-[3-(3,5-bis-phenylethynyl-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionicacid ethyl ester (example 83) (130 mg, 0.24 mmol) by a procedureanalogous to that described in example 26.

¹H NMR (CDCl₃, 300 MHz) δ: 1.18 (t, 3H), 2.96 (dd, 1H), 3.98 (dd, 1H),3.37-3.48 (m, 1H), 3.53-3.67 (m, 1H), 4.03 (dd, 1H), 4.68 (d, 2H), 6.47(dt, 1H), 6.68 (d, 1H), 6.88 (d, 2H), 7.18 (d, 2H), 7.30-7.42 (m, 6H),7.48-7.58 (m, 6H), 7.60 (s, 1H).

Example 85

(E)-(S)-3-{4-[3-(3,5-Diphenethyl-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionicacid ethyl ester

a)

A solution of 3,5-distyryl-benzaldehyde (2.0 g, 6.44 mmol) (prepared asdescribed in example 79) in ethyl acetate (150 mL) was hydrogenated at 3atm for 16 h using 5% Pd-C (2 g) as catalyst. The catalyst was removedby filtration and the solvent evaporated to give(3,5-diphenethyl-phenyl)-methanol (2.0 g) as an oil.

b)

To a solution of (3,5-diphenethyl-phenyl)-methanol (2.0 g, 6.4 mmol) indry dichloromethane (30 mL) was added pyridinium chlorochromate (1.4 g,6.4 mmol) and the mixture was stirred at room temperature for 16 h. Theproduct was purified by flash chromatography using dichloromethane assolvent to give 1.3 g 3,5-diphenethyl-benzaldehyde.

c)

The title compound was prepared from 3,5-diphenethyl-benzaldehyde by asequence analogous to that described in example 23.

Example 86

(E)-(S)-3-{4-[3-(3,5-Diphenethyl-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionicacid

The title compound was prepared from(E)-(S)-3-{4-[3-(3,5-Diphenethyl-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionicacid ethyl ester (example 85) (449 mg, 0.80 mmol) by a procedureanalogous to that described in example 26.

¹H NMR (CDCl₃, 300 MHz) δ: 1.18 (t, 3H), 2.96 (dd, 1H), 3.08 (dd, 1H),3.35-3.48 (m, 1H), 3.55-3.67 (m, 1H), 4.03 (dd, 1H), 4.65 (dd, 1H), 6.35(dt, 1H), 6.68 (d, 1H), 6.82-6.92 (m, 3H), 7.04 (d, 2H), 7.12-7.32 (m,12H).

Example 87

3-{4-[3-(3,5-Bis-cyclopentyloxy-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionicacid ethyl ester

The title compound was prepared from dihydroxybenzaldehyde (1.0 g, 7.2mmol) and cyclopentylbromide (4.0 g, 29.0 mmol) by a sequence analogousto that described in example 75.

¹H NMR (CDCl₃, 300 MHz) δ: 1.18 (t, 3H), 1.21 (t, 3H), 1.50-1.68 (m,4H), 1.68-1.97 (m, 12H), 2.95 (d, 2H), 3.28-3.42 (m, 1H), 3.54-3.65 (m,1H), 3.97 (t, 1H), 4.15 (q, 2H), 4.67 (dd, 2H), 4.67-4.77 (m, 2H),6.28-6.40 (m, 2H), 6.50 (d, 2H), 6.60 (d, 1H), 6.87 (d, 2H), 7.15 (d,2H).

Example 88

(E)-(S)-3-{4-[3-(3,5-Bis-cyclopentyloxy-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionicacid

The title compound was prepared from(E)-(S)-3-{4-[3-(3,5-bis-cyclopentyloxy-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionicacid ethyl ester (example 87) (220 mg, 0.42 mmol) by a procedureanalogous to that described in example 26.

¹H NMR (CDCl₃, 300 MHz) δ: 1.18 (t, 3H), 1.52-1.70 (m, 4H), 1.70-1.98(m, 12H), 2.95 (dd, 1H), 3.07 (dd, 1H), 3.37-3.48 (m, 1H), 3.55-3.65 (m,1H), 4.03 (dd, 1H), 4.65 (dd, 2H), 4.70-4.78 (m, 2H), 6.29-6.40 (m, 2H),6.50 (d, 2H), 6.60 (d, 1H), 6.88 (d, 2H), 7.15 (d, 2H).

Example 89

(E)-(S)-3-(4-{3-[3,5-Bis-(2,2,2-trifluoro-ethoxy)-phenyl]-allyloxy}-phenyl)-2-ethoxy-propionicacid ethyl ester

a)

To a solution of 3,5-dihydroxybenzaldehyde (2.0 g, 14.5 mmol) in DMF (35mL) was added potassium carbonate (11.0 g, 80.0 mmol) and1,1,1-trifluoro-2-iodoethane (33.3 g, 160 mmol). The reaction mixturewas heated I a sealed reactor at 50° C. for 7 days. The mixture wasfiltered and washed with ethyl acetate. The filtrate was added water andthe organic phase isolated. The aqueous phase was extracted once morewith ethyl acetated. The combined organic phases were dried (MgSO₄),filtered and concentrated in vacuo. The residue was purified by flashchromatography eluting with toluene to give 906 mg (18%) of3,5-bis-(2,2,2-trifluoro-ethoxy)-benzaldehyde. ¹H NMR (CDCl₃, 300 MHz)δ: 4.43 (q, 4H), 6.85 (t, 1H), 7.15 (d, 2H), 9.95 (s, 1H).

b)

The title compound was prepared from3,5-bis-(2,2,2-trifluoro-ethoxy)-benzaldehyde by a sequence analogous tothat described in example 23.

¹H NMR (CDCl₃, 300 MHz) δ: 1.15 (t, 3H), 1.22 (t, 3H), 2.95 (d, 2H),3.30-3.40 (m, 1H), 3.55-3.67 (m, 1H), 3.97 (t, 1H), 4.15 (q, 2H), 4.33(q, 4H), 4.65 (d, 2H), 6.32-6.48 (m, 2H), 6.55-6.70 (m, 3H), 6.85 (d,2H), 7.15 (d, 2H).

Example 90

(E)-(S)-3-(4-{3-[3,5-Bis-(2,2,2-trifluoro-ethoxy)-phenyl]-allyloxy}-phenyl)-2-ethoxy-propionicacid

The title compound was prepared from(E)-(S)-3-(4-{3-[3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]-allyloxy}-phenyl)-2-ethoxy-propionicacid ethyl ester (example 89) (200 mg, 0.36 mmol) by a procedureanalogous to that described in example 26.

¹H NMR (CDCl₃, 300 MHz) δ: 1.20 (t, 3H), 2.97 (dd, 1H), 3.10 (dd, 1H),3.41-3.53 (m, 1H), 3.55-3.68 (m, 1H), 4.05 (dd, 1H), 4.35 (q, 4H), 4.67(d, 2H), 6.35-6.48 (m, 2H), 6.60-6.70 (m, 3H), 6.87 (d, 2H), 7.15 (d,2H).

Example 91

(E)-(S)-Ethyl2-Ethoxy-3-{4-[3-(4-furan-2-yl-phenyl)-but-2-enyloxy]-phenyl}-propionate

a)

Sodium (5.52 g, 0.24 mol) was added to ethanol (250 ml) at 20° C. andthe mixture stirred until the metal had fully reacted. Triethylphosphonoacetate (62.72 g, 0.28 mol) was added as an ethanol (50 ml)solution, the mixture stirred for 20 min, then a solution of4-iodoacetophenone (49.21 g, 0.20 mol) in ethanol (300 ml) was added andthe reaction mixture heated to 80° C. under reflux for 17 h. Thesolution was cooled, the ethanol evaporated and the resulting orangeresidue partitioned between 1N HCl (200 ml) and ethyl acetate (200 ml).The aqueous layer was collected and further extracted with ethyl acetate(3×200 ml). The organic layers were combined, washed with brine, dried(MgSO₄) and evaporated to an orange/yellow oil, which was purified bycolumn chromatography on silica gel (2% diethyl ether in n-heptaneeluent) to give the product, (E)-ethyl 3-(4-iodophenyl)-but-2-enoate, asa pale yellow oil; 54.83 g (87%)

¹H NMR (300 MHz, CDCl₃) δ: 1.31 (3H, t), 2.53 (3H, s), 4.21 (2H, q),6.11 (1H, s), 7.20 (2H, dm), 7.69 (2H, dm). ¹³CNMR (75 MHz, CDCl₃) δ:13.0 (q), 16.4 (q), 58.6 (t), 93.7 (s), 116.2 (d), 126.7 (d), 136.3 (d),140.3 (s), 152.8 (s), 165.2 (s). MS: 316 (M⁺), 287, 271, 244, 144, 115(100%). Microanalysis Calculated % C, 45.59; H, 4.14. Found % C, 45.72;H, 4.20.

b)

Tetrakis(triphenylphoshine)palladium(0) (0.69 g, 0.60 mmol, 6 mol %) wasadded, under nitrogen, to a stirred solution of (E)-ethyl3-(4-iodophenyl)-but-2-enoate (3.16 g, 10.0 mmol) in DME (100 ml), andthe resulting orange coloured solution stirred at room temperature for10 min. Aqueous 2M sodium carbonate (30.0 ml, 60.0 mmol) was then added,the mixture stirred for 10 min, then furan-2-boronic acid (2.25 g, 20.11mmol) was added, and the reaction mixture heated to 80° C. for 20 h,under reflux. The reaction mixture was cooled, diluted with water (100ml) and the products extracted into ethyl acetate (3×100 ml). Thecombined organic extracts were washed with brine, dried (MgSO₄), andevaporated to give the crude product, which was purified by columnchromatography on silica gel (3% diethyl ether in n-heptane eluent) togive the product, (E)-ethyl 3-(4-furan-2-yl-phenyl)-but-2-enoate as anoff-white solid; 2.46 g (96%).

Mpt. 85.5-56.5° C. ¹H NMR (300 MHz, CDCl₃) δ: 1.32 (3H, t), 2.59 (3H,d), 4.22 (2H, q), 6.18 (1H, m), 6.49 (1H, dd), 6.70 (1H, d), 7.46-7.56(3H, m), 7.66 (2H, dm). MS: 256 (100%, M⁺), 227, 211, 184, 153, 115.Microanalysis Calculated % C, 74.98; H, 6.29. Found % C, 74.99; H, 6.39.

c)

(E)-Ethyl 3-(4-furan-2-yl-phenyl)-but-2-enoate was reduced with DIBAL-Hby a procedure analogous to that described in example 50b, to give thecolourless solid (E)-3-(4-furan-2-yl-phenyl)-but-2-en-1-ol.

d)

The title compound (678 mg, 77%) was prepared from(E)-3-(4-furan-2-yl-phenyl)-but-2-en-1-ol (430 mg, 2.0 mmol) and(S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (526 mg, 2.21 mmol) bya procedure analogous to that described in example 52c.

¹H NMR (300 MHz, CDCl₃) δ: 1.17 (3H, t), 1.22 (3H, t), 2.14 (3H, d),2.96 (2H, d), 3.31-3.41 (1H, m), 3.55-3.66 (1H, m), 3.98 (1H, t), 4.16(2H, q), 4.73 (2H, d), 6.10 (1H, tm), 6.47 (1H, dd), 6.64 (1H, d), 6.88(2H, dm), 7.17 (2H, dm), 7.43-7.48 (3H, m), 7.62 (2H, dm). LCMS: 457(M+Na), 452 (M+NH₄), 197 (100%).

Example 92

(E)-(S)-Ethyl2-Ethoxy-3-{4-[3-(2′-methyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionate

a)

The colourless solid, (E)-ethyl 3-(2′-methyl-biphenyl-4-yl)-but-2-enoatewas prepared from (E)-ethyl 3-(4-iodophenyl)-but-2-enoate (example 91a)and ortho-tolyl boronic acid by a procedure analogous to that describedin example 91b.

b)

The colourless oil (E)-3-(2′-methyl-biphenyl-4-yl)-but-2-en-1-ol wasprepared by DIBAL-H reduction of (E)-ethyl3-(2′-methyl-biphenyl-4-yl)-but-2-enoate by a procedure analogous tothat described in example 50b.

c)

The title compound (1.80 g, 78%) was prepared as a colourless oil from(E)-3-(2′-methyl-biphenyl-4-yl)-but-2-en-1-ol (1.19 g, 4.99 mmol) and(S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (1.31 g, 6.48 mmol) bya procedure analogous to that described in example 52c.

¹H NMR (300 MHz, CDCl₃) δ: 1.17 (3H, t), 1.22 (3H, t), 2.17 (3H, d),2.28 (3H, s), 2.96 (2H, d), 3.30-3.41 (1H, m), 3.54-3.66 (1H, m), 3.98(1H, t), 4.16 (2H, q), 4.74 (2H, d), 6.11 (1H, tm), 6.88 (2H, dm), 7.16(2H, dm), 7.20-7.32 (6H, m), 7.47 (2H, dm). LCMS: 679 (M+221), 633(679-EtOH), 481 (M+Na), 476 (M+NH₄), 221 (100%).

Example 93

(E)-(S)-2-Ethoxy-3-{4-[3-(2′-methyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionicacid

The title compound was prepared by hydrolysis of (E)-(S)-ethyl2-ethoxy-3-{4-[3-(2′-methyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionate(example 92) (918 mg, 2.0 mmol) with sodium hydroxide by a procedureanalogous to that described in example 51, yielding(E)-(S)-2-ethoxy-3-{4-[3-(2′-methyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionicacid as a colourless gum, which contained 0.25 mol equivalents of ethylacetate; 586 mg (64%).

¹H NMR (300 MHz, CDCl₃) δ: 1.17 (3H, t), 1.27 (0.75H, t, AcOEt), 2.04(0.75H, s, AcOEt), 2.19 (3H, d), 2.29 (3H, s), 2.96 (1H, dd), 3.09 (1H,dd), 3.41-3.53 (1H, m), 3.53-3.65 (1H, m), 4.06 (1H, dd), 4.12 (0.5H, q,AcOEt), 4.75 (2H, d), 6.12 (1H, tm), 6.89 (2H, dm), 7.16 (2H, dm),7.20-7.34 (6H, m), 7.48 (2H, dm), carboxylic acid proton not observed.LCMS: 651 (M+221), 453 (M+Na), 221 (100%).

Example 94

(E)-(S)-Ethyl3-{4-[3-(2′,5′-Dimethoxy-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate

a)

The colourless oil, (E)-ethyl3-(2′,5′-dimethoxy-biphenyl-4-yl)-but-2-enoate was prepared from(E)-ethyl 3-(4-bromophenyl)-but-2-enoate (example 50a) and2,5-dimethoxyphenyl boronic acid by a procedure analogous to thatdescribed in example 52a.

b)

The colourless gum (E)-3-(2′,5′-dimethoxy-biphenyl-4-yl)-but-2-en-1-olwas prepared by DIBAL-H reduction of (E)-ethyl3-(2′,5′-dimethoxy-biphenyl-4-yl)-but-2-enoate by a procedure analogousto that described in example 52b.

c)

The title compound (0.765 g, 61%) was prepared as a colourless gum from(E)-3-(2′,5′-dimethoxy-biphenyl-4-yl)-but-2-en-1-ol (0.711 g, 2.50 mmol)and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.655 g, 2.75mmol) by a procedure analogous to that described in example 52c.

¹H NMR (300 MHz, CDCl₃) δ: 1.17 (3H, t), 1.22 (3H, t), 2.16 (3H, d),2.96 (2H, d), 3.31-3.41 (1H, m), 3.55-3.65 (1H, m), 3.76 (3H, s), 3.81(3H, s), 3.98 (1H, t), 4.17 (2H, q), 4.74 (2H, d), 6.10 (1H, tm),6.81-6.95 (5H, m), 7.16 (2H, dm), 7.45-7.53 (4H, m). LCMS: 771 (M+267),527 (M+Na), 422 (M+NH₄), 267 (100%).

Example 95

(E)-(S)-3-{4-[3-(2′,5′-Dimethoxy-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid

The title compound was prepared from (E)-(S)-ethyl3-{4-[3-(2′,5′-dimethoxy-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate(Example 94) (0.62 g, 1.23 mmol) and sodium hydroxide (1M, 2.0 ml, 2.0mmol) by a procedure analogous to that described in example 51, yielding(E)-(S)-ethyl3-{4-[3-(2′,5′-dimethoxy-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid as a colourless glass; 0.485 g (83%).

¹H NMR (300 MHz, CDCl₃) δ: 1.18 (3H, t), 2.16 (3H, d), 2.96 (1H, dd),3.10 (1H, dd), 3.42-3.51 (1H, m), 3.51-3.65 (1H, m), 3.75 (3H, s), 3.80(3H, s), 4.05 (1H, dd), 4.74 (2H, d), 6.10 (1H, tm), 6.81-6.94 (5H, m),7.17 (2H, dm), 7.43-7.53 (4H, m), carboxylic acid proton not observed.LCMS: 743 (M+267), 499 (M+Na), 494 (M+NH₄), 267 (100%).

Example 96

(E)-(S)-Ethyl3-{4-[3-(4-Bromophenyl)-2-ethyl-but-2-enyloxy]-phenyl}-2-ethoxy-propionate

a)

A solution of triethyl 2-phosphonobutyrate (17.7 g, 70.0 mmol) in dryTHF (30 ml) was added dropwise, at 0° C., to a stirred suspension ofsodium hydride (50% dispersion in mineral oil, 2.90 g, 60.4 mmol) in dryTHF (30 ml) and the mixture stirred for 30 min. A solution of4-bromoacetophenone (7.96 g, 39.99 mmol) in THF (80 ml) was added over20 min., the resulting mixture warmed to room temperature and stirringcontinued overnight. Second portions of triethyl 2-phosphonobutyrate(10.11 g, 40.1 mmol) and sodium hydride (2.90 g, 60.4 mmol) were thenadded at room temperature, and stirring continued for a further 24 h;TLC at this stage showed that a substantial amount of unreacted 4-bromoacetophenone starting material was still present. The reaction wasworked up by adding 1N HCl (200 ml) and ethyl acetate (100 ml), theorganic layer collected and the aqueous layer extracted with ethylacetate (3×100 ml). The combined organic layers were washed with brine,dried (MgSO₄) and concentrated to give an orange gum, which was purifiedby column chromatography on silica gel (2% diethyl ether in n-heptaneeluent) to give the orange oil, (E/Z)-ethyl3-(4-bromophenyl)-2-ethyl-but-2-enoate (3.47 g, 29%) as a mixture ofdouble-bond isomers.

b)

A toluene solution of DIBAL-H (1M, 29.0 ml, 29.0 mmol) was addeddropwise at −70° C. to a stirred THF (100 ml) solution of (E/Z)-ethyl3-(4-bromophenyl)-2-ethyl-but-2-enoate (3.45 g, 11.6 mmol), and thesolution stirred for 40 min. Methanol (1 ml) was carefully added,followed by 1N HCl (300 ml) and ethyl acetate (200 ml). The aqueouslayer was separated and further extracted with ethyl acetate (2×150 ml).The combined organic layers were washed with brine, dried (MgSO₄), andconcentrated to give an orange gum, which was separated into its twomajor constituents by column chromatography on silica gel (15% ethylacetate in n-heptane eluent). The two products, in order of elution,were (Z)-3-(4-bromo-phenyl)-2-ethyl-but-2-en-1-ol (0.365 g, 12%) and(E)-3-(4-bromophenyl)-2-ethyl-but-2-en-1-ol (0.89 g, 30%).

c)

The title compound (843 mg, 89%) was prepared from(E)-3-(4-bromophenyl)-2-ethyl-but-2-en-1-ol (510 mg, 2.0 mmol) and(S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (500 mg, 2.10 mmol) bya procedure analogous to that described in example 52c.

¹H NMR (300 MHz, CDCl₃) δ: 0.94 (3H, t), 1.20 (3H, t), 1.23 (3H, t),2.01 (3H, s), 2.05 (2H, q), 2.97 (2H, d), 3.31-3.43 (1H, m), 3.54-3.68(1H, m), 3.99 (1H, t), 4.17 (2H, q), 4.61 (2H, s), 6.89 (2H, dm), 7.04(2H, dm), 7.18 (2H, dm), 7.45 (2H, dm).

Example 97

(E)-(S)-3-{4-[3-(4-Bromophenyl)-2-ethyl-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid

The title compound was prepared from (E)-(S)-ethyl3-{4-[3-(4-bromophenyl)-2-ethyl-but-2-enyloxy]-phenyl}-2-ethoxy-propionate(Example 96) (0.78 g, 1.64 mmol) and sodium hydroxide (1M, 3.3 ml, 3.3mmol) by a procedure analogous to that described in example 51, yielding(E)-(S)-3-{4-[3-(4-bromophenyl)-2-ethyl-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid (0.703 g, 96%) as a pale yellow oil, which contained a small amountof dichloromethane; 0.703 g (96%).

¹H NMR (300 MHz, CDCl₃) δ: 1.19 (3H, t), 1.26 (ethyl acetate impurity,0.6H, t), 2.04 (ethyl acetate impurity, 0.4H, s), 2.16 (3H, s), 2.96(1H, dd), 3.10 (1H, dd), 3.42-3.52 (1H, m), 3.53-3.68 (1H, m), 3.80 (3H,s), 4.07 (1H, dd), 4.12 (ethyl acetate impurity, 0.4H), 4.74 (2H, d),5.30 (CH₂Cl₂, trace), 6.10 (1H, t), 6.85-6.95 (3H, m), 7.12-7.20 (2H,m), 7.21-7.32 (2H, m), 7.45-7.50 (4H, m), carboxylic acid proton notobserved.

Example 98

(Z)-(S)-Ethyl3-{4-[3-(4-Bromophenyl)-2-ethyl-but-2-enyloxy]-phenyl}-2-ethoxy-propionate

The title compound (535 mg, 81%) was prepared from(Z)-3-(4-bromophenyl)-2-ethyl-but-2-en-1-ol (prepared as described inexample 96b) (355 mg, 1.39 mmol) and (S)-ethyl2-ethoxy-3-(4-hydroxyphenyl)-propionate (348 mg, 1.46 mmol) by aprocedure analogous to that described in example 52c.

¹H NMR (300 MHz, CDCl₃) δ: 1.11 (3H, t), 1.16 (3H, t), 1.21 (3H, t),2.04 (3H, s), 2.37 (2H, q), 2.93 (2H, d), 3.29-3.40 (1H, m), 3.53-3.65(1H, m), 3.95 (1H, t), 4.16 (2H, q), 4.25 (2H, s), 6.70 (2H, dm),7.03-7.12 (4H, m), 7.40 (2H, dm). Microanalysis Calculated % C, 63.16;H, 6.57. Found % C, 63.34; H, 6.66.

Example 99

(Z)-(S)-3-{4-[3-(4-Bromophenyl)-2-ethyl-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid

The title compound was prepared from (Z)-(S)-ethyl3-{4-[3-(4-bromophenyl)-2-ethyl-but-2-enyloxy]-phenyl}-2-ethoxy-propionate(Example 98) (475 mg, 1.0 mmol) and sodium hydroxide (1M, 2.0 ml, 2.0mmol) by a procedure analogous to that described in example 51, yielding(Z)-(S)-3-{4-[3-(4-bromophenyl)-2-ethyl-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid (0.424 g, 95%) as a pale yellow oil.

¹H NMR (300 MHz, CDCl₃) δ: 1.11 (3H, t), 1.18 (3H, t), 2.04 (3H, s),2.37 (2H, q), 2.94 (1H, dd), 3.04 (1H, dd), 3.40-3.53 (1H, m), 3.53-3.64(1H, m), 4.03 (1H, dd), 4.25 (2H, s), 6.71 (2H, dm), 7.02-7.14 (4H, m),7.40 (2H, dm), carboxylic acid proton not observed.

Example 100

(E)-(S)-Ethyl3-{4-[3-(4′-tert-Butyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate

a)

The colourless oil, (E)-ethyl3-(4′-tert-butyl-biphenyl-4-yl)-but-2-enoate was prepared from (E)-ethyl3-(4-bromophenyl)-but-2-enoate (example 50a) and4-tert-butylphenylboronic acid by a procedure analogous to thatdescribed in example 52a

b)

The colourless gum (E)-3-(4′-tert-butyl-biphenyl-4-yl)-but-2-en-1-ol wasprepared by DIBAL-H reduction of (E)-ethyl3-(4′-tert-butyl-biphenyl-4-yl)-but-2-enoate by a procedure analogous tothat described in example 52b.

c)

The title compound (0.375 g, 75%) was prepared as a colourless gum from(E)-3-(4′-tert-butyl-biphenyl-4-yl)-but-2-en-1-ol (0.280 g, 1.00 mmol)and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.250 g, 1.05mmol) by a procedure analogous to that described in example 52c.

¹H NMR (300 MHz, CDCl₃) δ: 1.17 (3H, t), 1.22 (3H, t), 1.37 (9H, s),2.17 (3H, d), 2.97 (2H, d), 3.30-3.43 (1H, m), 3.53-3.67 (1H, m), 3.98(1H, t), 4.17 (2H, q), 4.73 (2H, d), 6.11 (1H, tm), 6.88 (2H, dm), 7.17(2H, dm), 7.43-7.60 (8H, m). LCMS: 763 (M+263), 523 (M+Na), 263 (100%).

Example 101

(E)-(S)-Ethyl3-{4-[3-(3′,5′-Bis-trifluoromethyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate

a)

The colourless solid, (E)-ethyl3-(3′,5′-bis-trifluoromethyl-biphenyl-4-yl)-but-2-enoate was preparedfrom (E)-ethyl 3-(4-iodophenyl)-but-2-enoate (example 91a) and3,5-bis-(trifluoromethyl)phenyl boronic acid by a procedure analogous tothat described in example 91b.

b)

The colourless solid(E)-3-(3′,5′-bis-trifluoromethyl-biphenyl-4-yl)-but-2-en-1-ol wasprepared by DIBAL-H reduction of (E)-ethyl3-(3′,5′-bis-trifluoromethyl-biphenyl-4-yl)-but-2-enoate by a procedureanalogous to that described in example 50b.

c)

The title compound (656 mg, 81%) was prepared as a colourless oil from(E)-3-(3′,5′-bis-trifluoromethyl-biphenyl-4-yl)-but-2-en-1-ol (500 mg,1.39 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (348mg, 1.46 mmol) by a procedure analogous to that described in example52c.

¹H NMR (300 MHz, CDCl₃) δ: 1.17 (3H, t), 1.23 (3H, t), 2.18 (3H, d),2.97 (2H, d), 3.30-3.43 (1H, m), 3.56-3.69 (1H, m), 3.98 (1H, t), 4.17(2H, q), 4.75 (2H, d), 6.15 (1H, tm), 6.89 (2H, dm), 7.18 (2H, dm),7.52-7.62 (4H, m), 7.85 (1H, s), 8.01 (2H, s). LCMS: 603 (100%, M+Na),598 (M+NH₄), 343.

Example 102

(E)-(S)-3-{4-[3-(3′,5′-Bis-trifluoromethyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid

The title compound was prepared from (E)-(S)-ethyl3-{4-[3-(3′,5′-bis-trifluoromethyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate(Example 101) (625 mg, 1.08 mmol) and sodium hydroxide (1M, 4.3 ml, 4.3mmol) by a procedure analogous to that described in example 51, yielding(E)-(S)-3-{4-[3-(3′,5′-bis-trifluoromethyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid (535 mg, 90%) as a colourless gum.

¹H NMR (300 MHz, CDCl₃) δ: 1.20 (3H, t), 2.18 (3H, d), 2.98 (1H, dd),3.10 (1H, dd), 3.43-3.53 (1H, m), 3.53-3.66 (1H, m), 4.07 (1H, dd), 4.76(2H, d), 6.15 (1H, tm), 6.90 (2H, dm), 7.19 (2H, dm), 7.50-7.62 (4H, m),7.85 (1H, s), 8.01 (2H, s), carboxylic acid proton not observed.

Example 103

(E)-(S)-Ethyl2-Ethoxy-3-{4-[3-(4′-isopropyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionate

a)

The colourless solid, (E)-ethyl3-(4′-isopropyl-biphenyl-4-yl)-but-2-enoate was prepared from (E)-ethyl3-(4-bromophenyl)-but-2-enoate (example 50a) and 4-isopropylphenylboronic acid by a procedure analogous to that described in example 52a.

Mpt. 96.5-97.5° C. ¹H NMR (300 MHz, CDCl₃) δ: 1.29 (6H, d), 1.32 (3H,t), 2.61 (3H, d), 2.97 (1H, septet), 4.22 (2H, q), 6.20 (1H, m), 7.32(2H, dm), 7.50-7.65 (6H, m). MS: 308 (100%, M⁺), 293, 178. MicroanalysisCalculated % C, 81.78; H, 7.84. Found % C, 81.96; H, 8.22.

b)

The colourless solid (E)-3-(4′-isopropyl-biphenyl-4-yl)-but-2-en-1-olwas prepared by DIBAL-H reduction of (E)-ethyl3-(4′-isopropyl-biphenyl-4-yl)-but-2-enoate by a procedure analogous tothat described in example 50b.

Mpt. 110.5-112.5° C. ¹H NMR (300 MHz, CDCl₃) δ: 1.29 (6H, d), 2.10 (3H,s), 2.94 (1H, septet), 4.37 (2H, d), 6.03 (1H, t), 7.29 (2H, dm),7.40-7.60 (6H, m). MS: 266 (M⁺), 251 (M-Me), 223 (100%, M-i-Pr).Microanalysis Calculated % C, 85.67; H, 8.32. Found % C, 85.55; H, 8.55.

c)

The title compound (410 mg, 84%) was prepared as a colourless solid from(E)-3-(4′-isopropyl-biphenyl-4-yl)-but-2-en-1-ol (266 mg, 1.00 mmol) and(S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (250 mg, 1.05 mmol) bya procedure analogous to that described in example 52c.

Mpt. 70-73° C. ¹H NMR (300 MHz, CDCl₃) δ: 1.17 (3H, t), 1.22 (3H, t),1.29 (6H, d), 2.17 (3H, d), 2.89-3.01 (3H, m), 3.30-3.41 (1H, m),3.55-3.66 (1H, m), 3.98 (1H, t), 4.17 (2H, q), 4.74 (2H, d), 6.11 (1H,tm), 6.88 (2H, dm), 7.17 (2H, dm), 7.30 (2H, dm), 7.46-7.57 (6H, m).LCMS: 735 (M+249), 509 (M+Na), 249 (100%).

Example 104

(E)-(S)-2-Ethoxy-3-{4-[3-(4′-isopropyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionicacid

The title compound was prepared from (E)-(S)-ethyl2-ethoxy-3-{4-[3-(4′-isopropyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionate(Example 103) (400 mg, 0.822 mmol) and sodium hydroxide (1M, 3.29 ml,3.29 mmol) by a procedure analogous to that described in example 51,yielding(E)-(S)-2-ethoxy-3-{4-[3-(4′-isopropyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionicacid (380 mg, 100%) as a beige coloured solid.

¹H NMR (300 MHz, CDCl₃) δ: 1.19 (3H, t), 1.29 (6H, d), 2.17 (3H, d),2.89-3.01 (2H, m), 3.10 (1H, dd), 3.42-3.64 (2H, m), 4.06 (1H, dd), 4.74(2H, d), 6.11 (1H, tm), 6.90 (2H, dm), 7.16 (2H, dm), 7.30 (2H, dm),7.46-7.57 (6H, m), carboxylic acid proton not observed. LCMS: 707(M+249), 481 (M+Na), 249 (100%).

Example 105

(E)-(S)-3-{4-[3-(3,5-Dimethoxy-phenyl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid ethyl ester

The title compound was prepared from 3′,5′-dimethoxyacetophenone (7.0 g,0.0388 mol) by a sequence analogous to that described in example 3,yielding 0.165 g (35%) of(E)-(S)-3-{4-[3-(3,5-Dimethoxy-phenyl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid ethyl ester.

¹H NMR (200 MHz, CDCl₃) δ: 1.1-1.27 (6H, m), 2.97 (2H, d), 3.3-3.4 (1H,m), 3.52-3.7 (1H, m), 4.0 (1H, t), 4.15 (2H, q), 4.7 (2H, d),), 6.39(1H, dd), 6.57 (2H, dd), 6.88 (2H, d), 7.17 (2H, d).

Example 106

(E)-(S)-3-{4-[3-(3′-Acetyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid

The title compound was prepared from (E)-(S)-ethyl3-{4-[3-(3′-acetyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate(Example 105) (140 mg, 0.288 mmol) and sodium hydroxide (1M, 0.58 ml,0.58 mmol) by a procedure analogous to that described in example 51,yielding(E)-(S)-3-{4-[3-(3′-acetyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid (33 mg, 25%) as a yellow coloured solid.

¹H NMR (300 MHz, CDCl₃) δ: 1.19 (3H, t), 2.18 (3H, d), 2.66 (3H, s),2.97 (1H, dd), 3.10 (1H, dd), 3.41-3.65 (2H, m), 4.07 (1H, dd), 4.75(2H, d), 6.13 (1H, tm), 6.90 (2H, dm), 7.17 (2H, dm), 7.49-7.63 (5H, m),7.80 (1H, dm), 7.93 (1H, dm), 8.19 (1H, m), carboxylic acid proton notobserved. LCMS: 707 (M+249), 481 (M+Na), 249 (100%).

Example 107

(E)-(S)-Ethyl3-{4-[3-(4′-Acetyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate

a)

(E)-3-(4-Iodophenyl)-but-2-en-1-ol was prepared by DIBAL-H reduction of(E)-ethyl 3-(4-iodophenyl)-but-2-enoate (example 91a) by a procedureanalogous to that described in example 50b.

¹H NMR (300 MHz, CDCl₃) δ: 1.36 (1H, br s), 2.04 (3H, d), 2.66 (3H, s),4.36 (2H, br d), 5.96 (1H, tm), 7.15 (2H, dm), 7.65 (2H, dm).

b)

The pale yellow solid,(E)-1-[4′-(3-hydroxy-1-methyl-propenyl)-biphenyl-4-yl]-ethanone wasprepared from 4-acetylphenyl boronic acid and(E)-3-(4-iodophenyl)-but-2-en-1-ol by a procedure analogous to thatdescribed in example 54a.

¹H NMR (300 MHz, CDCl₃) δ: 1.55 (1H, br s), 2.12 (3H, d), 2.64 (3H, s),4.41 (2H, d), 6.07 (1H, tm), 7.52 (2H, dm), 7.61 (2H, dm), 7.70 (2H,dm), 8.03 (2H, dm).

c)

The title compound (275 mg, 75%) was prepared from(E)-1-[4′-(3-hydroxy-1-methyl-propenyl)-biphenyl-4-yl]-ethanone (200 mg,0.75 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (188mg, 0.79 mmol) by a procedure analogous to that described in example52c.

¹H NMR (300 MHz, CDCl₃) δ: 1.17 (3H, t), 1.23 (3H, t), 2.18 (3H, d),2.64 (3H, s), 2.97 (2H, d), 3.30-3.42 (1H, m), 3.55-3.67 (1H, m), 3.98(1H, t), 4.17 (2H, q), 4.75 (2H, d), 6.14 (1H, tm), 6.89 (2H, dm), 7.17(2H, dm), 7.54 (2H, dm), 7.61 (2H, dm), 7.70 (2H, dm), 8.03 (2H, dm).

Example 108

(E)-(S)-3-{4-[3-(4′-Acetyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid

The title compound was prepared from (E)-(S)-ethyl3-{4-[3-(4′-acetyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate(Example 107) (200 mg, 0.411 mmol) and sodium hydroxide (1M, 1.64 ml,1.64 mmol) by a procedure analogous to that described in example 51,yielding(E)-(S)-3-{4-[3-(4′-acetyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid (70 mg, 37%) as a yellow coloured solid.

¹H NMR (300 MHz, CDCl₃) δ: 1.19 (3H, t), 2.18 (3H, d), 2.64 (3H, s),2.97 (1H, dd), 3.11 (1H, dd), 3.45-3.65 (2H, m), 4.08 (1H, dd), 4.75(2H, d), 6.14 (1H, tm), 6.90 (2H, dm), 7.17 (2H, dm), 7.54 (2H, dm),7.61 (2H, dm), 7.70 (2H, dm), 8.03 (2H, dm), carboxylic acid proton notobserved. LCMS: 707 (M+249), 459 (M+H), 249 (100%).

Example 109

(E)-(S)-Ethyl2-Ethoxy-3-[4-(3-[1,1′;3′,1″]terphenyl-5′-yl-allyloxy)-phenyl]-propionate

a)

Sodium (0.90 g, 39.1 mmol) was added to ethanol (50 ml) at 20° C. andthe mixture stirred until the metal had fully reacted. Triethylphosphonoacetate (10.1 g, 45 mmol) was added, the mixture stirred. for10 min, then a solution of 3,5-dibromobenzaldehyde (7.92 g, 30 mmol) inethanol (50 ml) was added and the reaction mixture heated to 80° C.under reflux for 72 h. The solution was cooled, the ethanol evaporatedand the resulting yellow residue partitioned between 1N HCl (100 ml) andethyl acetate (100 ml). The aqueous layer was collected and furtherextracted with ethyl acetate (3×100 ml). The organic layers werecombined, washed with brine, dried (MgSO₄) and evaporated to a yellowsolid, which was purified by column chromatography on silica gel (2%diethyl ether in n-heptane eluent) to give the product, (E)-ethyl3-(3,5-dibromophenyl)-acrylate, as a colourless solid; 4.54 g (45%).

Mpt. 80-82° C. ¹H NMR (300 MHz, CDCl₃) δ: 1.33 (3H, t), 4.27 (2H, q),6.42 (1H, d), 7.51 (1H, d), 7.58 (2H, d), 7.66 (1H, t). MS: 336/334/332(M⁺), 308/306/304, 291/289/287 (100%, M-Oet), 180/182.

b)

The colourless solid, (E)-ethyl 3-[1,1′;3′,1″]terphenyl-5′-yl-acrylatewas prepared from (E)-ethyl 3-(3,5-dibromophenyl)-acrylate andphenylboronic acid by a procedure analogous to that described in example52a.

Mpt. 78.5-81.5° C. ¹H NMR (300 MHz, CDCl₃) δ: 1.36 (3H, t), 4.29 (2H,q), 6.58 (1H, d), 7.33-7.54 (6H, m), 7.60-7.68 (4H, m), 7.72 (2H, d),7.81 (1H, t), 7.82 (1 H, d). MS: 328 (100%, M⁺), 283, 256, 252, 241,239.

c)

The colourless solid (E)-3-[1,1′;3′,1″]terphenyl-5′-yl-prop-2-en-1-olwas prepared by DIBAL-H reduction of (E)-ethyl3-[1,1′;3′,1″]terphenyl-5′-yl-acrylate by a procedure analogous to thatdescribed for example 52b.

Mpt. 140-141.5° C. ¹H NMR (300 MHz, CDCl₃) δ: 1.54 (1H, br s), 4.38 (2H,d), 6.50 (1H, dt), 6.75 (1H, d), 7.30-7.52 (6H, m), 7.53-7.73 (7H, m).MS: 286 (M⁺), 258 (100%), 243, 230, 165, 91, 77.

d)

The title compound (426 mg, 80%) was prepared from(E)-3-[1,1′;3′,1″]terphenyl-5′-yl-prop-2-en-1-ol (300 mg, 1.05 mmol) and(S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (262 mg, 1.10 mmol) bya procedure analogous to that described in example 52c.

¹H NMR (300 MHz, CDCl₃) δ: 1.16 (3H, t), 1.22 (3H, t), 2.96 (2H, d),3.29-3.41 (1H, m), 3.54-3.66 (1H, m), 3.98 (1H, t), 4.16 (2H, q), 4.73(2H, d), 6.54 (1H, dt), 6.85 (1H, d), 6.90 (2H, dm), 7.17 (2H, dm),7.30-7.50 (6H, m), 7.55-7.71 (7H, m). LCMS: 775 (M+269), 729 (100%,M+269-EtOH), 461 (M+H-EtOH), 269.

Example 110

(E)-(S)-2-Ethoxy-3-[4-(3-[1,1′;3′,1″]terphenyl-5′-yl-allyloxy)-phenyl]-propionicacid

The title compound was prepared from (E)-(S)-ethyl2-ethoxy-3-[4-(3-[1,1′;3′,1″]terphenyl-5′-yl-allyloxy)-phenyl]-propionate(Example 109) (405 mg, 0.8 mmol) and sodium hydroxide (1M, 1.6 ml, 1.6mmol) by a procedure analogous to that described in example 51, yielding(E)-(S)-2-ethoxy-3-[4-(3-[1,1′;3′,1″]terphenyl-5′-yl-allyloxy)-phenyl]-propionicacid (352 mg, 92%) as a colourless glass.

¹H NMR (300 MHz, CDCl₃) δ: 1.18 (3H, t), 2.97 (1H, dd), 3.09 (1H, dd),3.41-3.53 (1H, m), 3.53-3.65 (1H, m), 4.07 (1H, dd), 4.73 (2H, dd), 6.54(1H, dt), 6.85 (1H, dm), 6.92 (2H, dm), 7.17 (2H, dm), 7.32-7.50 (6H,m), 7.55-7.71 (7H, m), carboxylic acid proton not observed. LCMS: 747(M+269), 501 (M+Na), 496 (M+NH₄), 269 (100%).

Example 111

(E,E)-(S)-Ethyl3-(4′-{3-[4-(2-Ethoxy-2-ethoxycarbonyl-ethyl)-phenoxy]-1-methyl-propenyl}-biphenyl-3-yl)-but-2-enoate

a)

The yellow oil (E,E)-ethyl3-[4′-(3-hydroxy-1-methyl-propenyl)-biphenyl-3-yl]-but-2-enoate wasprepared from(E)-1-[4′-(3-hydroxy-1-methyl-propenyl)-biphenyl-3-yl]-ethanone (example105a) and triethyl phosphonoacetate by a reaction analogous to thatdescribed for example 50a.

¹H NMR (300 MHz, CDCl₃) δ: 1.33 (3H, t), 1.37 (1H, br t), 2.13 (3H, d),2.62 (3H, d), 4.23 (2H, q), 4.41 (2H, br t), 6.06 (1H, tm), 6.19 (1H,m), 7.40-7.62 (7H, m), 7.68 (1H, m). MS: 336 (M⁺), 334, 308, 293, 43(100%).

b)

The title compound (230 mg, 58%) was prepared from (E,E)-ethyl3-[4′-(3-hydroxy-1-methyl-propenyl)-biphenyl-3-yl]-but-2-enoate (235 mg,0.70 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (175mg, 0.73 mmol) by a procedure analogous to that described in example52c.

¹H NMR (300 MHz, CDCl₃) δ: 1.17 (3H, t), 1.23 (3H, t), 1.33 (3H, t),2.17 (3H, d), 2.62 (3H, d), 2.96 (2H, d), 3.30-3.42 (1H, m), 3.55-3.67(1H, m), 3.98 (1H, t), 4.17 (2H, q), 4.23 (2H, q), 4.75 (2H, d), 6.13(1H, tm), 6.20 (1H, m), 6.89 (2H, dm), 7.17 (2H, dm), 7.42-7.62 (7H, m),7.67 (1H, m). MS: 556 (M⁺), 319 (100%).

Example 112

(E,E)-(S)-3-(4′-{3-[4-(2-Carboxy-2-ethoxy-ethyl)-phenoxy]-1-methyl-propenyl}-biphenyl-3-yl)-but-2-enoicacid

The title compound was prepared from (E,E)-(S)-ethyl3-(4′-{3-[4-(2-ethoxy-2-ethoxycarbonyl-ethyl)-phenoxy]-1-methyl-propenyl}-biphenyl-3-yl)-but-2-enoate(example 111) (190 mg, 0.34 mmol) and sodium hydroxide (1M, 1.4 ml, 1.4mmol) by a procedure analogous to that described in example 51, yielding(E,E)-(S)-3-(4′-{3-[4-(2-carboxy-2-ethoxy-ethyl)-phenoxy]-1-methyl-propenyl}-biphenyl-3-yl)-but-2-enoicacid (135 mg, 79%) as a colourless solid.

¹H NMR (300 MHz, CDCl₃) δ: 1.19 (3H, t), 2.18 (3H, m), 2.64 (3H, s),3.01 (1H, dd), 3.08 (1H, dd), 3.40-3.70 (2H, m), 4.07 (1H, dd), 4.75(2H, dd), 6.12 (1H, br m), 6.23 (1H, s), 6.89 (2H, dm), 7.18 (2H, dm),7.40-7.70 (8H, m), carboxylic acid protons not observed.

Example 113

(E)-(S)-Ethyl2-Ethoxy-3-{4-[3-(3′-methoxy-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionate

a)

The colourless oil (E)-ethyl 3-(3′-methoxy-biphenyl-4-yl)-but-2-enoatewas prepared from (E)-ethyl 3-(4-bromophenyl)-but-2-enoate (example 50a)and 3-methoxyphenyl boronic acid by a procedure analogous to thatdescribed in example 52a.

¹H NMR (300 MHz, CDCl₃) δ: 1.33 (3H, t), 2.61 (3H, d), 3.87 (3H, s),4.23 (2H, q), 6.20 (1H, m), 6.91 (1H, ddd), 7.13 (1H, dd), 7.19 (1H,ddd), 7.37 (1H, dd), 7.51-7.62 (4H, m). MS: 296 (100%, M⁺), 281, 267,251, 224. Microanalysis Calculated % C, 77.00; H, 6.80. Found % C,77.02; H, 6.93.

b)

The colourless solid (E)-3-(3′-methoxy-biphenyl-4-yl)-but-2-en-1-ol wasprepared by DIBAL-H reduction of (E)-ethyl3-(3′-methoxy-biphenyl-4-yl)-but-2-enoate as described for example 52b.

Mpt. 62-68° C. ¹H NMR (300 MHz, CDCl₃) δ: 1.40 (1H, br s), 2.12 (3H, d),3.87 (3H, s), 4.39 (2H, d), 6.05 (1H, tm), 6.89 (1H, ddd), 7.13 (1H,dd), 7.19 (1H, ddd), 7.35 (1H, dd), 7.49 (2H, dm), 7.56 (2H, dm). MS:254 (M⁺), 239, 211 (100%).

c)

The title compound (280 mg, 59%) was prepared as a colourless solid from(E)-3-(3′-methoxy-biphenyl-4-yl)-but-2-en-1-ol (254 mg, 1.00 mmol) and(S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (250 mg, 1.05 mmol) bya procedure analogous to that described in example 52c.

¹H NMR (300 MHz, CDCl₃) δ: 1.17 (3H, t), 1.22 (3H, t), 2.17 (3H, d),2.96 (2H, d), 3.30-3.42 (1H, m), 3.55-3.67 (1H, m), 3.87 (3H, s), 3.98(1H, t), 4.17 (2H, q), 4.74 (2H, d), 6.12 (1H, tm), 6.85-6.92 (3H, m),7.11-7.22 (4H, m), 7.35 (1H, dd), 7.47-7.59 (4H, m). MS: 474 (M⁺), 237(100%). Microanalysis Calculated % C, 75.92; H, 7.22. Found % C, 76.04;H, 7.39.

Example 114

(E)-(S)-2-Ethoxy-3-{4-[3-(3′-methoxy-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionicacid

The title compound was prepared from (E)-(S)-ethyl2-ethoxy-3-{4-[3-(3′-methoxy-biphenyl-4yl)-but-2-enyloxy]-phenyl}-propionate(example 113) (230 mg, 0.49 mmol) and sodium hydroxide (1M, 0.97 ml,0.97 mmol) by a procedure analogous to that described in example 51,yielding(E)-(S)-2-ethoxy-3-{4-[3-(3′-methoxy-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionicacid (183 mg, 85%) as a colourless solid.

¹H NMR (300 MHz, CDCl₃) δ: 1.18 (3H, t), 2.17 (3H, d), 2.97 (1H, dd),3.10 (1H, dd), 3.41-3.53 (1H, m), 3.53-3.65 (1H, m), 3.87 (3H, s), 4.07(1H, dd), 4.74 (2H, dd), 6.11 (1H, tm), 6.86-6.93 (3H, m), 7.11-7.22(4H, m), 7.35 (1H, dd), 7.47-7.59 (4H, m), carboxylic acid proton notobserved. LCMS: 683 (M+237), 469 (M+Na), 237 (100%).

Example 115

(E)-(S,S/R)-Ethyl2-Ethoxy-3-(4-{3-[3′-(1-hydroxy-ethyl)-biphenyl-4-yl]-but-2-enyloxy}-phenyl)-propionate

a)

The colourless solid(E)-(S/R)-3-[3′-(1-hydroxy-ethyl)-biphenyl-4-yl]-but-2-en-1-ol wasprepared by DIBAL-H reduction of(E)-1-[4′-(3-hydroxy-1-methyl-propenyl)-biphenyl-3-yl]-ethanone (example105a) by a procedure analogous to that described in example 52b.

Mpt. 94-100° C. ¹H NMR (300 MHz, DMSO-d₆) δ: 1.37 (3H, d), 2.02 (3H, d),4.18 (2H, br dd), 4.75 (1H, br t, OH), 4.78 (1H, dq), 5.21 (1H, d, OH),5.98 (1H, tm), 7.33 (1H, dm), 7.40 (1H, dd), 7.48-7.54 (3H, m),7.60-7.66 (3H, m). MS: 268 (100%, M⁺), 253, 235, 225. MicroanalysisCalculated % C, 80.56; H, 7.51. Found % C, 80.21; H, 7.78.

b)

The title compound (490 mg, 57%) was prepared as a colourless oil from(E)-(S/R)-3-[3′-(1-hydroxy-ethyl)-biphenyl-4-yl]-but-2-en-1-ol (500 mg,1.86 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (422mg, 1.77 mmol) by a procedure analogous to that described in example52c.

¹H NMR (300 MHz, CDCl₃) δ: 1.17 (3H, t), 1.22 (3H, t), 1.56 (3H, d),1.89 (1H, d, OH), 2.18 (3H, d), 2.97 (2H, d), 3.30-3.42 (1H, m),3.54-3.66 (1H, m), 3.98 (1H, t), 4.17 (2H, q), 4.75 (2H, d), 4.99 (1H,dq), 6.12 (1H, tm), 6.85 (2H, dm), 7.18 (2H, dm), 7.32-7.48 (2H, m),7.48-7.67 (6H, m).

Example 116

(E)-(S,S/R)-2-Ethoxy-3-(4-{3-[3′-(1-hydroxy-ethyl)-biphenyl-4-yl]-but-2-enyloxy}-phenyl)-propionicacid

The title compound was prepared from (E)-(S,S/R)-ethyl2-ethoxy-3-(4-{3-[3′-(1-hydroxy-ethyl)-biphenyl-4-yl]-but-2-enyloxy}-phenyl)-propionate(example 115) (460 mg, 0.94 mmol) and sodium hydroxide (1M, 1.9 ml, 1.9mmol) by a procedure analogous to that described in example 51, yielding(E)-(S,S/R)-ethyl2-ethoxy-3-(4-{3-[3′-(1-hydroxy-ethyl)-biphenyl-4-yl]-but-2-enyloxy}-phenyl)-propionicacid (434 mg, 100%) as a colourless gum.

¹H NMR (300 MHz, CDCl₃) δ: 1.18 (3H, t), 1.55 (3H, d), 2.17 (3H, d),2.96 (1H, dd), 3.09 (1H, dd), 3.41-3.53 (1H, m), 3.54-3.66 (1H, m), 4.06(1H, dd), 4.75 (2H, d), 4.98 (1H, q), 6.12 (1H, tm), 6.90 (2H, dm), 7.17(2H, dm), 7.32-7.46 (2H, m), 7.47-7.63 (6H, m), carboxylic acid protonnot observed.

Example 117

(E)-(S)-Ethyl3-{4-[3-(3,5-Dibromophenyl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate

a)

Sodium (0.49 g, 21.3 mmol) was added to ethanol (50 ml) at roomtemperature and the mixture stirred until the metal had fully reacted.Triethyl phosphonoacetate (5.49 g, 24.5 mmol) was added, the solutionstirred for 15 min, then an ethanol (100 ml) solution of3,5-dibromoacetophenone (4.60 g, 16.6 mol) was added and the reactionmixture heated to 80° C. under reflux for 72 h. The solution was cooled,the ethanol evaporated and the resulting orange residue partitionedbetween 1N HCl (150 ml) and ethyl acetate (150 ml). The aqueous layerwas collected and further extracted with ethyl acetate (2×100 ml). Theorganic layers were combined, washed with brine, dried (MgSO₄) andevaporated to an orange/yellow gum, which was purified by columnchromatography on silica gel (3% diethyl ether in n-heptane eluent) togive the product, (E)-ethyl 3-(3,5-dibromophenyl)-but-2-enoate, as acolourless wax; 4.06 g (70%).

¹H NMR (300 MHz, CDCl₃) δ: 1.32 (3H, t), 2.51 (3H, d), 4.22 (2H, q),6.09 (1H, m), 7.52 (2H, d), 7.64 (1H, t). MS: 350/348/346 (M⁺),304/302/300 (M-EtOH), 115 (100%). Microanalysis Calculated % C, 41.41;H, 3.48; Br, 45.92. Found % C, 41.75; H, 3.52; Br, 45.62.

b)

(E)-Ethyl 3-(3,5-dibromophenyl)-but-2-enoate was reduced with DIBAL-H bya procedure analogous to that described in example 50b, to give thecolourless oil (E)-3-(3,5-dibromophenyl)-but-2-en-1-ol.

¹H NMR (300 MHz, CDCl₃) δ: 1.64 (1H, br s), 2.01 (3H, d), 4.36 (2H, d),5.96 (1H, tm), 7.46 (2H, d), 7.54 (1H, t). MS: 308/306/304 (M⁺),293/291/289 (M-Me), 266/264/262, 227/225/223, 131, 128, 115 (100%), 102.

c)

The title compound (851 mg, 81%) was prepared from(E)-3-(3,5-dibromo-phenyl)-but-2-en-1-ol (612 mg, 2.0 mmol) and(S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (500 mg, 2.10 mmol) bya procedure analogous to that described in example 52c.

¹H NMR (300 MHz, CDCl₃) δ: 1.17 (3H, t), 1.23 (3H, t), 2.09 (3H, d),2.96 (2H, d), 3.30-3.42 (1H, m), 3.54-3.66 (1H, m), 3.98 (1H, t), 4.17(2H, q), 4.69 (2H, d), 6.04 (1H, tm), 6.85 (2H, dm), 7.16 (2H, dm), 7.48(2H, d), 7.57 (1H, t). LCMS: 551/549/547 (100%, M+Na), 546/544/542(M+NH₄), 483/481/479 (M+H-EtOH).

Example 118

(E)-(S)-3-{4-[3-(3,5-Dibromophenyl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid

The title compound was prepared from (E)-(S)-ethyl3-{4-[3-(3,5-dibromophenyl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate(example 117) (840 mg, 1.60 mmol) and sodium hydroxide (1M, 16 ml, 16mmol) by a procedure analogous to that described in example 51, yielding(E)-(S)-3-{4-[3-(3,5-dibromophenyl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid (781 mg, 98%) as a colourless gum.

¹H NMR (300 MHz, CDCl₃) δ: 1.19 (3H, t), 2.08 (3H, d), 2.96 (1H, dd),3.09 (1H, dd), 3.41-3.53 (1H, m), 3.55-3.67 (1H, m), 4.07 (1H, dd), 4.70(2H, d), 6.04 (1H, tm), 6.87 (2H, dm), 7.17 (2H, dm), 7.48 (2H, d), 7.58(1H, t), carboxylic acid proton not observed. LCMS: 523/521/519 (100%,M+Na), 518/516/514 (M+NH₄), 455/453/451 (M+H-EtOH), 291/289/287.

Example 119

(E)-(S)-Ethyl3-{4-[3-(3,5-Dibromophenyl)-allyloxy]-phenyl}-2-ethoxy-propionate

a)

(E)-Ethyl 3-(3,5-dibromophenyl)-acrylate (example109a) was reduced withDIBAL-H by a procedure analogous to that described in example 50b, togive the colourless solid (E)-3-(3,5-dibromophenyl)-prop-2-en-1-ol.

¹H NMR (300 MHz, CDCl₃) δ: 1.52 (1H, t, OH), 4.35 (2H, ddd), 6.36 (1H,dt), 6.50 (1H, dm), 7.44 (2H, d), 7.53 (1H, t). LCMS: 277/275/273 (100%,M+H-H₂O), 196/194 (M+H-H₂O—Br), 100.

b)

The title compound (780 mg, 78%) was prepared from(E)-3-(3,5-dibromophenyl)-prop-2-en-1-ol (584 mg, 2.0 mmol) and(S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (500 mg, 2.10 mmol) bya procedure analogous to that described in example 52c.

¹H NMR (300 MHz, CDCl₃) δ: 1.17 (3H, t), 1.22 (3H, t), 2.96 (2H, d),3.30-3.42 (1H, m), 3.55-3.67 (1H, m), 3.97 (1H, t), 4.17 (2H, q), 4.68(2H, dd), 6.41 (1H, dt), 6.59 (1H, dm), 6.86 (2H, dm), 7.17 (2H, dm),7.46 (2H, d), 7,53 (1H, t).

Example 120

(E)-(S)-3-{4-[3-(3,5-Dibromophenyl)-allyloxy]-phenyl}-2-ethoxy-propionicacid

The title compound was prepared from (E)-(S)-ethyl 3-(4-[3-(3,5-dibromophenyl)-allyloxy]-phenyl}-2-ethoxy-propionate (example 119)(512 mg, 1.0 mmol) and sodium hydroxide (1M, 10 ml, 10 mmol) by aprocedure analogous to that described in example 51, yielding(E)-(S)-3-{4-[3-(3,5-dibromophenyl)-allyloxy]-phenyl}-2-ethoxy-propionicacid (96 mg, 20%) as a colourless gum.

¹H NMR (300 MHz, CDCl₃) δ: 1.19 (3H, t), 2.97 (1H, dd), 3.09 (1H, dd),3.40-3.66 (2H, m), 4.06 (1H, dd), 4.68 (2H, dd), 6.42 (1H, dt), 6.59(1H, dm), 6.88 (2H, dm), 7.18 (2H, dm), 7.46 (2H, d), 7.58 (1H, t),carboxylic acid proton not observed. LCMS: 509/507/505 (M+Na),504/502/500 (100%, M+NH₄), 441/439/437 (M+H-EtOH), 277/275/273.

Example 121

(E)-(S)-Ethyl3-{4-[3-(4,4″-Di-tert-butyl-[1,1′;3′,1″]terphenyl-5′-yl)-allyloxy]-phenyl}-2-ethoxy-propionate

a)

The colourless glass, (E)-ethyl3-(4,4″-di-tert-butyl-[1,1′;3′,1″]terphenyl-5′-yl)-acrylate was preparedfrom (E)-ethyl 3-(3,5-dibromophenyl)-acrylate (example 109a) and4-tert-butylphenylboronic acid by a procedure analogous to thatdescribed in example 52a.

¹H NMR (300 MHz, CDCl₃) δ: 1.36 (3H, t), 1.38 (18H, s), 4.29 (2H, q),6.55 (1H, d), 7.43-7.52 (4H, m), 7.52-7.61 (4H, m), 7.70 (2H, d), 7.81(1H, t), 7.82 (1H, d). MS: 440 (M⁺), 425 (100%, M-Me), 205.

b)

The colourless gum(E)-3-(4,4″-di-tert-butyl-[1,1′;3′,1″]terphenyl-5′-yl)-prop-2-en-1-olwas prepared by DIBAL-H reduction of (E)-ethyl3-(4,4″-di-tert-butyl-[1,1′;3′,1″]terphenyl-5′-yl)-acrylate by aprocedure analogous to that described for example 52b.

¹H NMR (300 MHz, CDCl₃) δ: 1.37 (18H, s), 1.48 (1H, br t), 4.37 (2H, m),6.49 (1H, dt), 6.75 (1H, dm), 7.45-7.52 (4H, m), 7.54-7.61 (6H, m), 7.68(1H, t). LCMS: 779 (M+381), 761 (779-H₂O), 437, 421 (M+Na), 399 (M+H,381 (100%, M+H-H₂O).

c)

The title compound (368 mg, 79%) was prepared from(E)-3-(4,4″-di-tert-butyl-[1,1′;3′,1″]terphenyl-5′-yl)-prop-2-en-1-ol(300 mg, 0.75 mmol) and (S)-ethyl2-ethoxy-3-(4-hydroxyphenyl)-propionate (188 mg, 0.79 mmol) by aprocedure analogous to that described in example 52c.

¹H NMR (300 MHz, CDCl₃) δ: 1.17 (3H, t), 1.22 (3H, t), 1.37 (18H, s),2.96 (2H, d), 3.30-3.43 (1H, m), 3.54-3.67 (1H, m), 3.98 (1H, t), 4.16(2H, q), 4.72 (2H, d), 6.52 (1H, dt), 6.85 (1H, d), 6.90 (2H, dm), 7.18(2H, dm), 7.44-7.52 (4H, m), 7.54-7.63 (6H, m), 7.69 (1H, m). LCMS: 641(100%, M+Na), 636 (M+NH₄), 381.

Example 122

(E)-(S)-3-{4-[3-(4,4″-Di-tert-butyl-[1,1′;3′,1″]terphenyl-5′-yl)-allyloxy]-phenyl}-2-ethoxy-propionicacid

The title compound was prepared from (E)-(S)-ethyl3-{4-[3-(4,4″-di-tert-butyl-[1,1′;3′,1″]terphenyl-5′-yl)-allyloxy]-phenyl}-2-ethoxy-propionate(example 121) (345 mg, 0.56 mmol) and sodium hydroxide (1M, 1.1 ml, 1.1mmol) by a procedure analogous to that described in example 51, yielding(E)-(S)-3-{4-[3-(4,4″-di-tert-butyl-[1,1′;3′,1″]terphenyl-5′-yl)-allyloxy]-phenyl}-2-ethoxy-propionicacid (284 mg, 86%) as a colourless foam.

¹H NMR (300 MHz, CDCl₃) δ: 1.18 (3H, t), 1.38 (18H, s), 2.97 (1H, dd),3.10 (1H, dd), 3.41-3.65 (2H, m), 4.07 (1H, dd), 4.72 (2H, dm), 6.52(1H, dt), 6.85 (1H, d), 6.92 (2H, dm), 7.17 (2H, dm), 7.44-7.52 (4H, m),7.55-7.62 (6H, m), 7.69 (1H, m), carboxylic acid proton not observed.

Example 123

(E)-(S)-Ethyl3-{4-[3-(3′,5′-Dibromo-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate

a)

The colourless gum (E)-ethyl3-(3′,5′-dibromo-biphenyl-4-yl)-but-2-enoate was prepared from (E)-ethyl3-(4-iodophenyl)-but-2-enoate (example 91a) and 3,5-dibromobenzeneboronic acid by a procedure analogous to that described in example 52a.

¹H NMR (300 MHz, CDCl₃) δ: 1.33 (3H, t), 2.61 (3H, d), 4.22 (2H, q),6.20 (1H, m), 7.44-7.80 (7H, m). LCMS: 427/425/423 (100%, M+H),381/379/377 (M+H-EtOH).

b)

The colourless gum (E)-3-(3′,5′-dibromo-biphenyl-4-yl)-but-2-en-1-ol wasprepared by DIBAL-H reduction of (E)-ethyl3-(3′,5′-dibromo-biphenyl-4-yl)-but-2-enoate as described for example52b, with the purification of the product being carried out bypreparative HPLC.

¹H NMR (300 MHz, CDCl₃) δ: 1.45 (1H, br s), 2.12 (3H, d), 4.41 (2H, d),6.05 (1H, tm), 7.45-7.54 (4H, m), 7.62 (1H, t), 7.66 (2H, d). LCMS:367/365/363 (100%, M+H-H₂O), 286/284.

c)

The title compound (177 mg, 83%) was prepared as a colourless gum from(E)-3-(3′,5′-dibromo-biphenyl-4-yl)-but-2-en-1-ol (135 mg, 0.35 mmol)and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (90 mg, 0.38 mmol)by a procedure analogous to that described in example 52c.

¹H NMR (300 MHz, CDCl₃) δ: 1.17 (3H, t), 1.23 (3H, t), 2.16 (3H, d),2.96 (2H, d), 3.31-3.43 (1H, m), 3.55-3.67 (1H, m), 3.98 (1H, t), 4.17(2H, q), 4.74 (2H, d), 6.13 (1H, tm), 6.88 (2H, dm), 7.17 (2H, dm),7.45-7.56 (4H, m), 7.63 (1H, t), 7.66 (2H, d). LCMS: 627/625/623 (100%,M+Na), 365.

Example 124

(E)-(S)-3-{4-[3-(3′,5′-Dibromo-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid

The title compound was prepared from (E)-(S)-ethyl3-{4-[3-(3′,5′-dibromo-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate(example 123) (110 mg, 0.18 mmol) and sodium hydroxide (1M, 1.0 ml, 1.0mmol) by a procedure analogous to that described in example 51, yielding(E)-(S)-3-{4-[3-(3′,5′-dibromo-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid (90 mg, 86%) as a colourless gum.

¹H NMR (300 MHz, CDCl₃) δ: 1.20 (3H, t), 2.18 (3H, d), 2.99 (1H, dd),3.12 (1H, dd), 3.43-3.68 (2H, m), 4.08 (1H, dd), 4.75 (2H, d), 6.13 (1H,tm), 6.91 (2H, dm), 7.19 (2H, dm), 7.45-7.60 (4H, m), 7.60-7.74 (3H, m),carboxylic acid proton not observed. LCMS: 599/597/595 (100%, M+Na),365.

Example 125

(E)-(S)-Ethyl3-{4-[3-(3′,5′-Dichloro-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate

a)

The colourless solid (E)-ethyl3-(3′,5′-dichloro-biphenyl-4-yl)-but-2-enoate was prepared from(E)-ethyl 3-(4-iodophenyl)-but-2-enoate (example 91 a) and3,5-dichlorobenzene boronic acid by a procedure analogous to thatdescribed in example 52a.

Mpt. 96.3-97.3° C. ¹H NMR (300 MHz, CDCl₃) δ: 1.33 (3H, t), 2.61 (3H,d), 4.23 (2H, q), 6.19 (1H, m), 7.35 (1H, t), 7.47 (2H, d), 7.51-7.61(4H, m). LCMS: 335/337/339 (100%, M+H), 289/291/293 (M+H-EtOH).Microanalysis Calculated % C, 64.49; H, 4.81; Cl, 21.15. found C, 64.41;H, 4.80; Cl, 20.80.

b)

The colourless oil (E)-3-(3′,5′-dichloro-biphenyl-4-yl)-but-2-en-1-olwas prepared by DIBAL-H reduction of (E)-ethyl3-(3′,5′-dichloro-biphenyl-4-yl)-but-2-enoate as described for example52b.

¹H NMR (300 MHz, CDCl₃) δ: 1.39 (1H, br s), 2.12 (3H, d), 4.40 (2H, d),6.05 (1H, tm), 7.33 (1H, t), 7.46 (2H, d), 7.45-7.65 (4H, m). MS:296/294/292 (100%, M⁺), 281/279/277 (M-Me), 278/276/274 (M−H₂O),253/251/249.

c)

The title compound (794 mg, 77%) was prepared as a colourless gum from(E)-3-(3′,5′-dichloro-biphenyl-4-yl)-but-2-en-1-ol (586 mg, 2.0 mmol)and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (500 mg, 2.10mmol) by a procedure analogous to that described in example 52c.

¹H NMR (300 MHz, CDCl₃) δ: 1.17 (3H, t), 1.23 (3H, t), 2.17 (3H, d),2.96 (2H, d), 3.30-3.42 (1H, m), 3.55-3.67 (1H, m), 3.98 (1H, t), 4.17(2H, q), 4.74 (2H, d), 6.13 (1H, tm), 6.88 (2H, dm), 7.18 (2H, dm), 7.33(1H, t), 7.46 (2H, d), 7.48-7.54 (4H, m). LCMS: 539/537/535 (100%,M+Na), 534/532/530 (M+NH₄), 279/277/275.

Example 126

(E)-(S)-3-{4-[3-(3′,5′-Dichloro-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid

The title compound was prepared from (E)-(S)-ethyl3-{4-[3-(3′,5′-dichloro-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate(example 125) (513 mg, 1.0 mmol) and sodium hydroxide (1M, 5.0 ml, 5.0mmol) by a procedure analogous to that described in example 51, yielding(E)-(S)-3-{4-[3-(3′,5′-dichloro-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid (422 mg, 87%) as a colourless glass.

¹H NMR (300 MHz, CDCl₃) δ: 1.19 (3H, t), 2.16 (3H, d), 2.97 (1H, dd),3.09 (1H, dd), 3.40-3.54 (H, m), 3.54-3.67 (1H, m), 4.07 (1H, dd), 4.74(2H, d), 6.12 (1H, tm), 6.90 (2H, dm), 7.18 (2H, dm), 7.32 (1H, t), 7.46(2H, d), 7.48-7.55 (4H, m), carboxylic acid proton not observed. LCMS:511/509/507 (100%, M+Na), 279/277/275.

Example 127

(E)-(S)-Ethyl3-{4-[3-(3′,5′-Dichloro-biphenyl-4-yl)-allyloxy]-phenyl}-2-ethoxy-propionate

a)

The colourless solid (E)-ethyl 3-(3′,5′-dichloro-biphenyl-4-yl)-acrylatewas prepared from (E)-ethyl 3-(4-bromo-phenyl)-acrylate (example 71a)and 3,5-dichlorobenzene boronic acid by a procedure analogous to thatdescribed in example 52a.

Mpt. 70-78° C. ¹H NMR (300 MHz, CDCl₃) δ: 1.35 (3H, t), 4.29 (2H, q),6.49 (1H, d), 7.36 (1H, t), 7.47 (2H, d), 7.53-7.64 (4H, m), 7.71 (1H,d). LCMS: 325/323/321 (100%, M+H). Microanalysis Calculated % C, 63.57;H, 4.39. found C, 63.37; H, 4.43.

b)

The colourless gum (E)-3-(3′,5′-dichloro-biphenyl-4-yl)-prop-2-en-1-olwas prepared by DIBAL-H reduction of (E)-ethyl3-(3′,5′-dichloro-biphenyl-4-yl)-acrylate as described for example 52b.

¹H NMR (300 MHz, CDCl₃) δ: 1.47 (1H, br t), 4.36 (2H, ddd), 6.43 (1H,dt), 6.65 (1H, dm), 7.33 (1H, t), 7.37-7.55 (6H, m). MS: 282/280/278(100%, M⁺), 239/237/235, 226/224/222.

c)

The title compound (732 mg, 70%) was prepared as a yellow gum,(containing 0.25 molar equivalents of ethyl acetate) from(E)-3-(3′,5′-dichloro-biphenyl-4-yl)-prop-2-en-1-ol (559 mg, 2.0 mmol)and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (500 mg, 2.10mmol) by a procedure analogous to that described in example 52c.

¹H NMR (300 MHz, CDCl₃) δ: 1.17 (3H, t), 1.22 (3H, t), 1.25 (0.75H, t,AcOEt), 2.04 (0.75H, s, AcOEt), 2.97 (2H, d), 3.30-3.41 (1H, m),3.53-3.67 (1H, m), 3.98 (1H, t), 4.12 (0.5H, q, AcOEt), 4.17 (2H, q),4.71 (2H, dd), 6.47 (1H, dt), 6.76 (1H, dm), 6.89 (2H, dm), 7.17 (2H,dm), 7.33 (1H, t), 7.43-7.55 (6H, m). LCMS: 525/523/521 (100%, M+Na),265/263/261.

Example 128

(E)-(S)-3-{4-[3-(3′,5′-Dichloro-biphenyl-4-yl)-allyloxy]-phenyl}-2-ethoxy-propionicacid

The title compound was prepared from (E)-(S)-ethyl3-{4-[3-(3′,5′-dichloro-biphenyl-4-yl)-allyloxy]-phenyl}-2-ethoxy-propionate(example 127) (522 mg, 1.0 mmol) and sodium hydroxide (1M, 10.0 ml, 10.0mmol) by a procedure analogous to that described in example 51, yielding(E)-(S)-3-{4-[3-(3′,5′-dichloro-biphenyl-4-yl)-allyloxy]-phenyl}-2-ethoxy-propionicacid (325 mg, 67%) as a colourless wax, which contained 0.167 molarequivalents of AcOEt.

¹H NMR (300 MHz, CDCl₃) δ: 1.19 (3H, t), 1.26 (0.5H, t, AcOEt), 2.04(0.5H, s, AcOEt), 2.97 (1H, dd), 3.09 (1H, dd), 3.41-3.53 (1H, m),3.53-3.68 (1H, m), 4.07 (1H, dd), 4.12 (0.33H, q, AcOEt), 4.71 (2H, dd),6.48 (1H, dt), 6.76 (1H, dm), 6.91 (2H, dm), 7.18 (2H, dm), 7.33 (1H,t), 7.40-7.60 (6H, m), carboxylic acid proton not observed. LCMS:497/495/493 (100%, M+Na), 492/490/488 (M+NH₄), 265/263/261.

Example 129

(E)-(S)-Ethyl3-{4-[3-(3′,5′-di-tert-butyl-biphenyl-4-yl)-allyloxy]-phenyl}-2-ethoxy-propionate

a)

The colourless solid (E)-3-(4-bromo-phenyl)-prop-2-en-1-ol was preparedby DIBAL-H reduction of (E)-ethyl 3-(4-bromo-phenyl)-acrylate (example71a) as described for example 52b.

Mpt. 65.5-67.5° C. ¹H NMR (300 MHz, CDCl₃) δ: 1.50 (1H, br s), 4.33 (2H,d), 6.35 (1H, dt), 6.55 (1H, d), 7.23 (2H, dm), 7.43 (2H, dm). MS:214/212 (M⁺), 171/169, 158/156, 133 (M−Br, 100%), 115, 91, 77.

b)

tert-Butyl chlorodimethylsilane (1.33 g, 19.5 mmol) was added to astirred solution of (E)-3-(4-bromo-phenyl)-prop-2-en-1-ol (3.20 g, 15.0mmol), and imidazole (2.72 g, 18.0 mmol) in dry dichloromethane (75 ml)and the resulting mixture stirred at room temperature for 18 h, acolourless precipitate being formed. The mixture was diluted withdichloromethane (100 ml) and 1N hydrochloric acid (100 ml). The aqueouslayer was separated, further extracted with dichloromethane (2×100ml)and the combined organic layers washed with brine, dried (MgSO₄) andevaporated. The product was purified by column chromatography on silicagel (1% diethyl ether in n-heptane eluent) to give the colourless solid,(E)-[3-(4-bromo-phenyl)-allyloxy]-tert-butyldimethylsilane (4.39 g,89%).

Mpt. 46.5-48° C. ¹H NMR (300 MHz, CDCl₃) δ: 0.11 (6H, s), 0.94 (9H, s),4.34 (2H, dd), 6.27 (1H, dt), 6.54 (1H, dt), 7.24 (2H, dm), 7.42 (2H,dm), 7.71 (1H, d). Microanalysis Calculated % C, 55.04; H, 7.08, Br,24.41. found C, 54.81; H, 7.22, Br, 24.51.

c)

tert-Butyllithium (1.7M in pentane, 3.5 ml, 6.0 mmol) was addeddropwise, at −78° C. to a stirred THF (10 ml) solution of(E)-[3-(4-bromo-phenyl)-allyloxy]-tert-butyldimethylsilane (982 mg, 3.0mmol) and the resulting solution stirred for 45 min. Trimethylborate(0.51 ml, 4.50 mmol) was added, the solution allowed to warm to roomtemperature over 2h, and the solvents evaporated to give the crudeboronate ester as a yellow gum, which was dissolved in DME (10 ml).Tetrakis(triphenylphosphine)palladium(0) (69 mg, 0.06 mmol), was addedto a stirred DME (20 ml) solution of 1-bromo-3,5-di-tert-butylbenzene(538 mg, 2.0 mmol), the solution stirred for 10 min, aqueous sodiumcarbonate (2M, 9 ml, 18.0 mmol) added, and stirring continued for afurther 10 min. The boronate ester solution was added and the mixtureheated to 80° C., under reflux, for 24 h. The resulting mixture wasdiluted with 1N HCl (50 ml), the products extracted into ethyl acetate(3×50 ml), and the combined extracts washed with brine, dried (MgSO₄),and evaporated. The resulting yellow gum was dissolved in dry THF (20ml), tetra-n-butyl ammonium fluoride (1.26 g, 4.0 mmol) added and thesolution stirred at room temperature for 18h. The resulting mixture wasdiluted with 1N HCl (50 ml), and the products extracted into ethylacetate (2×50 ml). The combined organic phases were washed with brine,dried (MgSO₄), and evaporated to give the colourless glass,(E)-3-(3′,5′-di-tert-butyl-biphenyl-4-yl)-prop-2-en-1-ol (127 mg, 20%).

¹H NMR (300 MHz, CDCl₃) δ: 1.38 (18H, s), 1.45 (1H, br t), 4.35 (2H, brt), 6.41 (1H, dt), 6.66 (1H, br dm), 7.40-7.49 (5H, m), 7.53-7.58 (2H,m). MS: 322 (M⁺), 307 (100%, M-Me), 57.

d)

The title compound (110 mg, 51%) was prepared as a colourless gum from(E)-3-(3′,5′-di-tert-butyl-biphenyl-4-yl)-prop-2-en-1-ol (127 mg, 0.39mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (99 mg, 0.41mmol) by a procedure analogous to that described in example 52c.

¹H NMR (300 MHz, CDCl₃) δ: 1.17 (3H, t), 1.23 (3H, t), 1.38 (18H, s),2.97 (2H, d), 3.29-3.42 (1H, m), 3.53-3.67 (1H, m), 3.98 (1H, t), 4.17(2H, q), 4.70 (2H, dd), 6.45 (1H, dt), 6.77 (1H, dm), 6.90 (2H, dm),7.18 (2H, dm), 7.40-7.60 (7H, m).

Example 130

(E)-(S)-3-{4-[3-(3′,5′-Di-tert-butyl-biphenyl-4-yl)-allyloxy]-phenyl}-2-ethoxy-propionicacid

The title compound was prepared from (E)-(S)-ethyl3-{4-[3-(3′,5′-di-tert-butyl-biphenyl-4-yl)-allyloxy]-phenyl}-2-ethoxy-propionate(example 129) (110 mg, 0.20 mmol) and sodium hydroxide (1M, 0.8 ml, 0.8mmol) by a procedure analogous to that described in example 51, yielding((E)-(S)-3-{4-[3-(3′,5′-di-tert-butyl-biphenyl-4-yl)-allyloxy]-phenyl}-2-ethoxy-propionicacid (92 mg, 88%) as a colourless solid.

¹H NMR (300 MHz, CDCl₃) δ: 1.20 (3H, t), 1.38 (18H, s), 2.97 (1H, dd),3.10 (1H, dd), 3.40-3.65 (2H, m), 4.07 (1H, dd), 4.70 (2H, dd), 6.45(1H, dt), 6.77 (1H, dm), 6.90 (2H, dm), 7.18 (2H, dm), 7.38-7.60 (7H,m), carboxylic acid proton not observed.

Example 131

(E)-(S)-Ethyl3-{4-[3-(3′,5′-Di-tert-butyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate

a)

The colourless oil,(E)-[3-(4-bromophenyl)-but-2-enyloxy]-tert-butyl-dimethylsilane wasprepared from (E)-3-(4-bromophenyl)-but-2-en-1-ol (example 50b),imidazole and tert-butyl chlorodimethylsilane by a procedure analogousto that described in example 129b.

¹H NMR (300 MHz, CDCl₃) δ: 0.10 (6H, s), 0.92 (9H, s), 4.37 (2H, d),5.88 (1H, tm), 7.25 (2H, dm), 7.42 (2H, dm). MS: 342/340 (M⁺), 327/325(M-Me), 285/283 (M-Bu), 130, 75 (100%).

b)

The colourless wax,(E)-3-(3′,5′-di-tert-butyl-biphenyl-4-yl)-but-2-en-1-ol was prepared viaa metallation, boronation, cross coupling and deprotection sequenceanalogous to that described for example 129c.

¹H NMR (300 MHz, CDCl₃) δ: 1.26 (1H, br m), 1.38 (18H, s), 2.12 (3H, d),4.40 (2H, br t), 6.05 (1H, dt), 7.40-7.42 (3H, m), 7.43-7.59 (4H, m).LCMS: 331 (M+H), 319 (100%, M+H-H₂O).

c)

The title compound (429 mg, 74%) was prepared as a colourless gum from(E)-3-(3′,5′-di-tert-butyl-biphenyl-4-yl)-but-2-en-1-ol (350 mg, 1.04mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (260 mg,1.09 mmol) by a procedure analogous to that described in example 52c.

¹H NMR (300 MHz, CDCl₃) δ: 1.17 (3H, t), 1.22 (3H, t), 1.38 (18H, s),2.17 (3H, d), 2.96 (2H, d), 3.30-3.43 (1H, m), 3.55-3.68 (1H, m), 3.98(1H, t), 4.17 (2H, q), 4.75 (2H, d), 6.11 (1H, tm), 6.89 (2H, dm), 7.17(2H, dm), 7.40-7.45 (3H, m), 7.46-7.60 (4H, m). LCMS: 579 (100%, M+Na),574 (M+NH₄), 511 (M+H-EtOH).

Example 132

(E)-(S)-3-{4-[3-(3′,5′-Di-tert-butyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid

The title compound was prepared from (E)-(S)-ethyl3-{4-[3-(3′,5′-di-tert-butyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate(example 131) (400 mg, 0.72 mmol) and sodium hydroxide (1M, 2.9 ml, 2.9mmol) by a procedure analogous to that described in example 51, yielding(E)-(S)-3-{4-[3-(3′,5′-di-tert-butyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionicacid (315 mg, 83%) as a colourless gum.

¹H NMR (300 MHz, CDCl₃) δ: 1.19 (3H, t), 1.39 (18H, s), 2.18 (3H, d),2.97 (1H, dd), 3.10 (1H, dd), 3.40-3.67 (2H, m), 4.07 (1H, dd), 4.70(2H, d), 6.11 (1H, tm), 6.90 (2H, dm), 7.18 (2H, dm), 7.40-7.45 (3H, m),7.46-7.60 (4H, m), carboxylic acid proton not observed. LCMS: 847(M+319), 551 (M+Na), 319 (100%).

Example 133

(E)-(S/R)-Ethyl3-[4-(3-Biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-isopropoxy-propionate

a)

(S/R)-Ethyl 2-(diethoxyphosphoryl)-2-isopropoxy-acetate was prepared asa pale green oil by the rhodium(II) acetate dimer catalysed reaction ofethyl diazo-(diethoxyphosphoryl)-acetate with isopropyl alcohol,according to the method described by C. J. Moody et al (Tetrahedron,1992, 48, 3991-4004).

¹H NMR (300 MHz, CDCl₃) δ: 1.21 (3H, d), 1.23 (3H, d), 1.28-1.39 (9H,m), 3.74 (1H, septet), 4.15-4.35 (6H, m), 4.39 (1H, d, J_(HP)=19.9 Hz).LCMS: 283 (M+H), 241 (100%), 213.

b)

A THF (20 ml) solution of (S/R)-ethyl2-(diethoxyphosphoryl)-2-isopropoxy-acetate (6.40 g, 22.7 mmol) wasadded dropwise, at 0° C., to a stirred suspension of sodium hydride (60%dispersion in mineral oil, 0.92 g, 23.0 mmol) in THF (20 ml), and theresulting mixture stirred for 30 min. A THF (20 ml) solution of4-benzyloxybenzaldehyde (3.21 g, 15.1 mmol) was added, the resultingsolution allowed to warm to room temperature, and stirring continued for72 h. The mixture was carefully diluted with 1N HCl (150 ml), theproducts extracted into ethyl acetate (3×100 ml), and the combinedorganic phases washed with brine, dried (MgSO₄) and (MgSO₄) andevaporated to give a yellow gum, which was purified by columnchromatography on silica gel (10% ethyl acetate in n-heptane eluent) togive the intermediate, (E/Z)-ethyl3-(4-benzyloxyphenyl)-2-isopropoxy-acrylate as a colourless gum. The(E/Z)-ethyl 3-(4-benzyloxyphenyl)-2-isopropoxy-acrylate was dissolved inethanol (100 ml), palladium on activated charcoal (10 wt. %, 0.80 g,0.75 mmol) added and the mixture hydrogenated at 30 lb/in² H₂ pressurefor 18 h. The catalyst was removed by filtration through celite and thesolvent evaporated to give (S/R)-ethyl3-(4-hydroxyphenyl)-2-isopropoxy-propionate (3.44 g, 90%) as a paleorange gum.

¹H NMR (300 MHz, CDCl₃) δ: 0.98 (3H, d), 1.15 (3H, d), 1.24 (3H, t),2.82-2.98 (2H, m), 3.51 (1H, septet), 4.02 (1H, dd), 4.17 (2H, q), 5.49(1H, br s), 6.75 (2H, dm), 7.09 (2H, dm). LCMS: 275 (M+Na), 253 (M+H),235, 211, 193, 151, 137 (100%).

c)

The title compound (324 mg, 70%) was prepared as a colourless solid from(S/R)-ethyl 3-(4-hydroxyphenyl)-2-isopropoxy-propionate (280 mg, 1.11mmol) and (E)-3-biphenyl-4-yl-but-2-en-1-ol (225 mg, 1.0 mmol) by aprocedure analogous to that described in example 52c.

Mpt. 79-81° C. ¹H NMR (300 MHz, CDCl₃) δ: 0.97 (3H, d), 1.16 (3H, d),1.24 (3H, t), 2.17 (3H, d), 2.85-3.02 (2H, m), 3.51 (1H, septet), 4.01(1H, dd), 4.08-4.25 (2H, m), 4.75 (2H, d), 6.11 (1H, tm), 6.88 (2H, dm),7.17 (2H, dm), 7.30-7.38 (1H, m), 7.40-7.65 (8H, m). LCMS: 665 (M+207),481 (M+Na), 476 (M+NH₄), 207 (100%).

Example 134

(E)-(S/R)-3-[4-(3-Biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-isopropoxy-propionicacid

The title compound was prepared from (E)-(S/R)-ethyl3-[4-(3-biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-isopropoxy-propionate(example 133) (230 mg, 0.50 mmol) and sodium hydroxide (1M, 1.5 ml, 1.5mmol) by a procedure analogous to that described in example 51, yielding(E)-(S/R)-3-[4-(3-biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-isopropoxy-propionicacid (190 mg, 88%) as a colourless solid.

Mpt. 125-127.5° C. ¹H NMR (300 MHz, CDCl₃) δ: 1.03 (3H, d), 1.16 (3H,d), 2.17 (3H, d), 2.90 (1H, dd), 3.08 (1H, dd), 3.55 (1H, septet), 4.10(1H, dd), 4.75 (2H, d), 6.12 (1H, tm), 6.90 (2H, dm), 7.17 (2H, dm),7.30-7.38 (1H, m), 7.40-7.65 (8H, m), carboxylic acid proton notobserved. LCMS: 637 (M+207), 453 (M+Na), 448 (M+NH₄), 207 (100%).

Example 135

(E)-(S/R)-Ethyl3-[4-(3-Biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-butoxy-propionate

a)

Butyl di-butoxy acetate (23.75 g, 91.2 mmol) was mixed with acetylchloride (15.5 ml, 218 mmol) and iodine (0.2 g, 0.79 mmol) and theresulting brown solution heated to 60° C., under reflux, for 6 h. Theproduct was then fractionally distilled, under reduced pressure,yielding

(S/R)-butyl 2-butoxy-2-chloro-acetate (17.58 g, 79%) as an orangecoloured oil. Bpt. 130-135° C./approx. 15 mmHg. ¹H NMR (300 MHz, CDCl₃)δ: 0.89-0.99 (6H, m), 1.41 (4H, sextet), 1.60-1.75 (4H, m), 3.60 (1H,dt), 3.98 (1H, dt), 4.25 (2H, t), 5.81 (1H, s).

b)

A mixture of triethylphosphite (13.05 ml, 75.0 mmol) and (S/R)-butyl2-butoxy-2-chloro-acetate (16.70 g, 75.0 mmol) was heated to 140° C.,under reflux, for 6 h. The resulting oil was fractionally distilledunder reduced pressure to give the product, (S/R)-butyl2-butoxy-2-(diethoxyphosphoryl)-acetate (20.42 g, 84%) as a colourlessoil.

Bpt. 170-175° C./1-5 mmHg. ¹H NMR (300 MHz, CDCl₃) δ: 0.87-0.99 (6H, m),1.30-1.49 (10H, m), 1.57-1.73 (4H, m), 3.52 (1H, dt), 3.66 (1H, dt),4.15-4.30 (6H, m), 4.30 (1H, d, J_(HP)=19 Hz). LCMS: 325 (100%, M+H),269, 167.

c)

A THF (40 ml) solution of (S/R)-butyl2-butoxy-2-(diethoxyphosphoryl)-acetate (14.60 g, 45.0 mmol) was addeddropwise, at 0° C., to a stirred suspension of sodium hydride (55%dispersion in mineral oil, 2.61 g, 59.8 mmol) in THF (50 ml), and theresulting mixture stirred for 30 min. A THF (50 ml) solution of4-benzyloxybenzaldehyde (6.37 g, 30.0 mmol) was added, the resultingsolution allowed to warm to room temperature, and stirring continued for48 h. The mixture was carefully diluted with 1N HCl (200 ml), theproducts extracted into ethyl acetate (4×100 ml), and the combinedorganic phases washed with brine, dried (MgSO₄) and evaporated to give ayellow gum, which was purified by column chromatography on silica gel(10% ethyl acetate in n-heptane eluent) to give the intermediate,(E/Z)-butyl 3-(4-benzyloxyphenyl)-2-butoxy-acrylate as a colourless gum.

The (E/Z)-butyl 3-(4-benzyloxyphenyl)-2-butoxy-acrylate was dissolved inethanol (200 ml), palladium on activated charcoal (10 wt. %, 1.60 g, 1.5mmol) added and the mixture hydrogenated at 30 lb/in² H₂ pressure for 18h. The catalyst was removed by filtration through celite and the solventevaporated to give an orange gum, which contained both (S/R)-butyl3-(4-hydroxyphenyl)-2-butoxy-propionate and the trans-esterificationproduct, (S/R)-ethyl 3-(4-hydroxyphenyl)-2-butoxy-propionate. These wereseparated by column chromatography on silica gel (15% ethyl acetate inn-heptane eluent) to give, in respective order of elution, (S/R)-butyl3-(4-hydroxyphenyl)-2-butoxy-propionate (6.74 g, 76%) and (S/R)-ethyl3-(4-hydroxyphenyl)-2-butoxy-propionate (0.40 g, 5%) as colourless oils.

(S/R)-butyl 3-(4-hydroxyphenyl)-2-butoxy-propionate: ¹H NMR (300 MHz,CDCl₃) δ: 0.85 (3H, t), 0.91 (3H, t), 1.22-1.43 (4H, m), 1.43-1.65 (4H,m), 2.89-2.98 (2H, m), 3.28 (1H, dt), 3.54 (1H, dt), 3.97 (1H, dd), 4.11(2H, t), 5.56 (1H, br s), 6.74 (2H, dm), 7.08 (2H, dm). LCMS: 317(M+Na), 295 (M+H), 221 (100%, M+H-BuOH), 193, 179, 165, 137.

(S/R)-ethyl 3-(4-hydroxyphenyl)-2-butoxy-propionate: ¹H NMR (300 MHz,CDCl₃) δ: 0.85 (3H, t), 1.23 (3H, t), 1.21-1.39 (2H, m), 1.43-1.60 (2H,m), 2.89-2.99 (2H, m), 3.28 (1H, dt), 3.55 (1H, dt), 3.97 (1H, dd), 4.17(2H, q), 5.63 (1H, br s), 6.74 (2H, dm), 7.08 (2H, dm). LCMS: 289(M+Na), 267 (M+H), 193 (100%, M+H-BuOH), 151, 137.

d)

The title compound (420 mg, 71%) was prepared as a colourless solid from(S/R)-ethyl 3-(4-hydroxyphenyl)-2-butoxy-propionate (385 mg, 1.45 mmol)and (E)-3-biphenyl-4-yl-but-2-en-1-ol (280 mg, 1.25 mmol) by a procedureanalogous to that described in example 52c.

Mpt. 62-63.5° C. ¹H NMR (300 MHz, CDCl₃) δ: 0.85 (3H, t), 1.23 (3H, t),1.20-1.40 (2H, m), 2.17 (3H, d), 2.90-3.00 (2H, m), 3.27 (1H, dt), 3.55(1H, dt), 3.95 (1H, dd), 4.10-4.23 (2H, m), 4.74 (2H, d), 6.11 (1H, tm),6.88 (2H, dm), 7.17 (2H, dm), 7.30-7.38 (1H, m), 7.40-7.63 (8H, m).LCMS: 679 (M+207), 495 (M+Na), 490 (M+NH₄), 207 (100%).

Example 136

(E)-(S/R)-3-[4-(3-Biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-butoxy-propionicacid

The title compound was prepared from (E)-(S/R)-ethyl3-[4-(3-biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-butoxy-propionate(example 135) (331 mg, 0.70 mmol) and sodium hydroxide (1M, 2.1 ml, 2.1mmol) by a procedure analogous to that described in example 51, yielding(E)-(S/R)-3-[4-(3-biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-butoxy-propionicacid (42 mg, 13%) as a colourless solid.

¹H NMR (300 MHz, CDCl₃) δ: 0.87 (3H, t), 1.21-1.38 (2H, m), 1.47-1.60(2H, m), 2.17 (3H, br s), 2.96 (1H, dd), 3.09 (1H, dd), 3.33-3.44 (1H,m), 3.47-3.60 (1H, m), 4.04 (1H, dd), 4.75 (2H, d), 6.12 (1H, br t),6.90 (2H, dm), 7.17 (2H, dm), 7.30-7.38 (1H, m), 7.38-7.65 (8H, m),carboxylic acid proton not observed. LCMS: 651 (M+207), 467 (100%,M+Na), 207.

Example 137

(E)-(S/R)-Ethyl3-[4-(3-Biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-hexyloxy-propionate

a)

(S/R)-Ethyl 2-(diethoxyphosphoryl)-2-hexyloxy-acetate was prepared as apale green oil by the rhodium(II) acetate dimer catalysed reaction ofethyl diazo-(diethoxyphosphoryl)-acetate with 1-hexanol, by a methodanalogous to that described for example 133a.

¹H NMR (300 MHz, CDCl₃) δ: 0.88 (3H, t), 1.23-1.44 (15H, m), 1.57-1.69(2H, m), 3.51 (1H, dt), 3.65 (1H, dt), 4.15-4.38 (7H, m). LCMS: 671(2M+Na), 649 (2M+H), 325 (100%, M+H), 297, 241.

b)

Sodium hydride (60% dispersion in mineral oil, 1.0 g, 25.0 mmol) wasadded at 0° C., in small portions, to a stirred THF (50 ml) solution of(S/R)-ethyl 2-(diethoxyphosphoryl)-2-hexyloxy-acetate (8.12 g, 25.0mmol), and the resulting suspension stirred for 30 min. A THF (50 ml)solution of 4-benzyloxybenzaldehyde (4.25 g, 20.0 mmol) was added, theresulting solution allowed to warm to room temperature, and stirringcontinued for 4 h. The mixture was carefully diluted with 0.5N HCl (150ml), the products extracted into ethyl acetate (4×75 ml), and thecombined organic phases washed with brine, dried (MgSO₄) and evaporatedto give an orange coloured gum, which was purified by columnchromatography on silica gel (15% ethyl acetate in n-heptane eluent) togive the intermediate, (E/Z)-ethyl3-(4-benzyloxyphenyl)-2-hexyloxy-acrylate as a pale yellow oil.

The (E/Z)-ethyl 3-(4-benzyloxyphenyl)-2-hexyloxy-acrylate was dissolvedin ethanol (150 ml), palladium on activated charcoal (10 wt. %, 1.40 g,1.32 mmol) added and the mixture hydrogenated at 30 lb/in² H₂ pressurefor 18 h. The catalyst was removed by filtration through celite and thesolvent evaporated to give a colourless gum, which was purified bycolumn chromatography on silica gel (10% ethyl acetate in n-heptaneeluent) to give (S/R)-ethyl 3-(4-hydroxyphenyl)-2-hexyloxy-propionate(1.83 g, 30%) as a colourless gum.

¹H NMR (300 MHz, CDCl₃) δ: 0.85 (3H, t), 1.14-1.32 (9H, m), 1.45-1.60(2H, m), 2.94 (2H, d), 3.28 (1H, dt), 3.54 (1H, dt), 3.97 (1H, dd), 4.17(2H, q), 5.95 (1H, br s), 6.74 (2H, dm), 7.07 (2H, dm). MS: 294 (M⁺),221 (M−COOEt), 192 (M-hexanol), 137, 107 (100%).

c)

The title compound (248 mg, 81%) was prepared as a waxy solid from(S/R)-ethyl 3-(4-hydroxyphenyl)-2-hexyloxy-propionate (215 mg, 0.72mmol) and (E)-3-biphenyl-4-yl-but-2-en-1-ol (137 mg, 0.61 mmol) by aprocedure analogous to that described in example 52c.

¹H NMR (300 MHz, CDCl₃) δ: 0.86 (3H, t), 1.13-1.35 (9H, m), 1.46-1.60(2H, m), 2.17 (3H, br s), 2.88-3.00 (2H, m), 3.26 (1H, dt), 3.55 (1H,dt), 3.95 (1H, dd), 4.10-4.23 (2H, m), 4.74 (2H, d), 6.12 (1H, tm), 6.88(2H, dm), 7.17 (2H, dm), 7.30-7.37 (1H, m), 7.40-7.63 (8H, m).

Example 138

(E)-(S/R)-3-[4-(3-Biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-hexyloxy-propionicacid

The title compound was prepared from (E)-(S/R)-ethyl3-[4-(3-biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-hexyloxy-propionate(example 137) (172 mg, 0.34 mmol) and sodium hydroxide (1M, 1.0 ml, 1.0mmol) by a procedure analogous to that described in example 51, yielding(E)-(S/R)-3-[4-(3-biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-hexyloxy-propionicacid (160 mg, 99%) as a colourless solid.

Mpt. 117-119° C. ¹H NMR (300 MHz, CDCl₃) δ: 0.87 (3H, t), 1.13-1.38 (6H,m), 1.45-1.60 (2H, m), 2.17 (3H, d), 2.96 (1H, dd), 3.10 (1H, dd), 3.40(1H, dt), 3.53 (1H, dt), 4.05 (1H, dd), 4.75 (2H, d), 6.12 (1H, tm),6.90 (2H, dm), 7.16 (2H, dm), 7.30-7.38 (1H, m), 7.40-7.63 (8H, m),carboxylic acid proton not observed.

Example 139

(E)-(S/R)-Ethyl3-[4-(3-Biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-(3-phenyl-propoxy)-propionate

a)

(S/R)-Ethyl 2-(diethoxyphosphoryl)-2-(3-phenyl-propoxy)-acetate wasprepared as a pale green oil by the rhodium(II) acetate □immer catalysedreaction of 3-phenyl-1-propanol with ethyldiazo-(diethoxyphosphoryl)-acetate, by a method analogous to thatdescribed for example 133a.

¹H NMR (300 MHz, CDCl₃) δ: 1.23-1.40 (9H, m), 1.98 (2H, quintet), 2.72(2H, t), 3.52 (1H, dt), 3.67 (1H, dt), 4.15-4.35 (7H, m), 7.12-7.22 (3H,m), 7.22-7.32 (2H, m).

b)

A THF (50 ml) solution of (S/R)-ethyl2-(diethoxyphosphoryl)-2-(3-phenyl-propoxy)-acetate (14.2 g, 39.6 mmol)was added dropwise, at 0° C., to a stirred mixture of sodium hydride(60% dispersion in mineral oil, 2.35 g, 58.8 mmol) and4-benzyloxybenzaldehyde (4.20 g , 19.8 mmol) in THF (50 ml), and theresulting mixture allowed to warm slowly to room temperature over 18 h.The mixture was carefully diluted with water (150 ml), the productsextracted into ethyl acetate (2×150 ml), and the combined organic phaseswashed with brine, dried (MgSO₄) and evaporated to give (E/Z)-ethyl3-(4-benzyloxyphenyl)-2-(3-phenyl-propoxy)-acrylate as a yellow oil.

The (E/Z)-ethyl 3-(4-benzyloxyphenyl)-2-(3-phenyl-propoxy)-acrylate wasdissolved in ethanol (50 ml), palladium on activated charcoal (10 wt. %,1.0 g, 0.94 mmol) added and the mixture hydrogenated at 30 lb/in² H₂pressure for 18 h. The catalyst was removed by filtration through celiteand the solvent evaporated to give a colourless oil.

¹H NMR (300 MHz, CDCl₃) δ: 1.23 (3H, t), 1.72-1.97 (2H, m), 2.52-2.64(2H, m), 2.87-3.02 (2H, m), 3.17-3.27 (1H, m), 3.53-3.63 (1H, m), 3.94(1H, dd), 4.17 (2H, q), 4.93 (1H, s), 6.76 (2H, dm), 7.02-7.29 (7H, m).

c)

The title compound (150 mg, 56%) was prepared as a waxy solid from(S/R)-ethyl 3-(4-hydroxyphenyl)-2-(3-phenyl-propoxy)-propionate (172 mg,0.53 mmol) and (E)-3-biphenyl-4-yl-but-2-en-1-ol (112 mg, 0.50 mmol) bya procedure analogous to that described in example 52c.

¹H NMR (300 MHz, CDCl₃) δ: 1.23 (3H, t), 1.72-1.97 (2H, m), 2.16 (3H, brs), 2.51-2.65 (2H, m), 2.89-3.05 (2H, m), 3.17-3.27 (1H, m), 3.59 (1H,dt), 3.95 (1H, dd), 4.18 (2H, q), 4.74 (2H, d), 6.11 (1H, tm), 6.90 (2H,dm), 7.01-7.63 (16H, m). LCMS: 741 (M+207), 557 (100%, M+Na), 552(M+NH₄), 207.

Example 140

(E)-(S/R)-3-[4-(3-Biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-(3-phenyl-propoxy)-propionicacid

The title compound was prepared from (E)-(S/R)-ethyl3-[4-(3-biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-(3-phenyl-propoxy)-propionate(example 139) (130 mg, 0.24 mmol) and sodium hydroxide (1M, 0.73 ml,0.73 mmol) by a procedure analogous to that described in example 51,yielding(E)-(S/R)-3-[4-(3-biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-(3-phenyl-propoxy)-propionicacid (90 mg, 73%) as a colourless solid.

Mpt. 115-117° C. ¹H NMR (300 MHz, CDCl₃) δ: 1.75-1.98 (2H, m), 2.16 (3H,d), 2.52-2.68 (2H, m), 2.96 (1H, dd), 3.10 (1H, dd), 3.36 (1H, dt), 3.57(1H, dt), 4.03 (1H, dd), 4.74 (2H, d), 6.11 (1H, tm), 6.91 (2H, dm),7.06 (2H, dm), 7.12-7.63 (14H, m), carboxylic acid proton not observed.LCMS: 529 (M+Na), 525 (M+NH₄), 207 (100%).

Example 141

(E)-(S/R)-Ethyl3-[4-(3-Biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-(4-phenyl-butoxy)-propionate

a)

(S/R)-Ethyl 2-(diethoxyphosphoryl)-2-(4-phenyl-butoxy)-acetate wasprepared as a pale green oil by the rhodium(II) acetate □immer catalysedreaction of 4-phenyl-1-butanol with ethyldiazo-(diethoxyphosphoryl)-acetate, by a method analogous to thatdescribed for example 133a.

¹H NMR (300 MHz, CDCl₃) δ: 1.25-1.40 (9H, m), 1.60-1.78 (4H, m), 2.63(2H, t), 3.47-3.56 (1H, m), 3.61-3.70 (1H, m), 4.12-4.35 (7H, m),7.12-7.21 (3H, m), 7.21-7.31 (2H, m). LCMS: 745 (2M+H), 373 (100%, M+H),241.

b)

A THF (30 ml) solution of (S/R)-ethyl2-(diethoxyphosphoryl)-2-(4-phenyl-butoxy)-acetate (15.64 g, 42.0 mmol)was added dropwise, at 0° C., to a stirred suspension of sodium hydride(60% dispersion in mineral oil, 2.52 g, 63.0 mmol) in THF (30 ml), andthe resulting mixture stirred for 20 min. A THF (50 ml) solution of4-benzyloxybenzaldehyde (4.46 g, 21.0 mmol) was added, and the mixturewarmed, resulting in a vigorous reaction. The mixture was cooled,carefully diluted with 0.5N HCl (150 ml), the products extracted intoethyl acetate (2×150 ml), and the combined organic phases washed withbrine, dried (MgSO₄) and evaporated to give (E/Z)-ethyl3-(4-benzyloxyphenyl)-2-(4-phenyl-butoxy)-acrylate as a yellow oil. The(E/Z)-ethyl 3-(4-benzyloxyphenyl)-2-(4-phenyl-butoxy)-acrylate wasdissolved in ethanol (175 ml), palladium on activated charcoal (10 wt.%, 0.50 g, 0.47 mmol) added and the mixture hydrogenated at 30 lb/in² H₂pressure for 18 h. The catalyst was removed by filtration through celiteand the solvent evaporated to give a colourless gum, which was purifiedby column chromatography on silica gel to give (S/R)-ethyl3-(4-hydroxyphenyl)-2-(4-phenyl-butoxy)-propionate (1.73 g, 24%) as acolourless oil.

¹H NMR (300 MHz, CDCl₃) δ: 1.22 (3H, t), 1.50-1.67 (4H, m), 2.50-2.60(2H, m), 2.85-3.0 (2H, m), 3.21-3.31 (1H, m), 3.53-3.63 (1H, m), 3.94(1H, dd), 4.16 (2H, q), 6.72 (2H, dm), 7.06-7.31 (7H, m), phenol protonnot observed.

c)

The title compound (245 mg, 80%) was prepared as a yellow, waxy solidfrom (S/R)-ethyl 3-(4-hydroxyphenyl)-2-(4-phenyl-butoxy)-propionate (200mg, 0.58 mmol) and (E)-3-biphenyl-4-yl-but-2-en-1-ol (125 mg, 0.56 mmol)by a procedure analogous to that described in example 52c.

¹H NMR (300 MHz, CDCl₃) δ: 1.22 (3H, t), 1.50-1.68 (4H, m), 2.16 (3H,d), 2.50-2.60 (2H, m), 2.88-3.02 (2H, m), 3.21-3.33 (1H, m), 3.52-3.64(1H, m), 3.95 (1H, dd), 4.17 (2H, q), 4.72 (2H, d), 6.11 (1H, tm), 6.87(2H, dm), 7.06-7.63 (16H, m).

Example 142

(E)-(S/R)-3-[4-(3-Biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-(4-phenyl-butoxy)-propionicacid

The title compound was prepared from (E)-(S/R)-ethyl3-[4-(3-biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-(4-phenyl-butoxy)-propionate(example 141) (225 mg, 0.41 mmol) and sodium hydroxide (1M, 1.64 ml,1.64 mmol) by a procedure analogous to that described in example 51,yielding(E)-(S/R)-3-[4-(3-biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-(4-phenyl-butoxy)-propionicacid (210 mg, 99%) as a pale yellow solid.

¹H NMR (300 MHz, CDCl₃) δ: 1.50-1.70 (4H, m), 2.17 (3H, d), 2.53-2.61(2H, m), 2.95 (1H, dd), 3.09 (1H, dd), 3.34-3.44 (1H, m), 3.50-3.60 (1H,m), 4.04 (1H, dd), 4.72 (2H, d), 6.11 (1H, tm), 6.88 (2H, dm), 7.06-7.63(16H, m), carboxylic acid proton not observed.

Example 143

(E)-(S/R)-Propyl3-[4-(3-Biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-propoxy-propionate

a)

Morpholinium dimorpholinoacetate was prepared according to the methoddescribed by Bourguignon and Wermuth (Bourguignon, J. J.; Wermuth, C. G.J. Org. Chem. 1981, 46, 4889-4894): an ethanol (100 ml) solution ofmorpholine (310 ml, 3.55 mol) was added, at 0° C., to a stirred ethanol(500 ml) solution of glyoxylic acid monohydrate (92.06 g, 1.0 mol) andthe resulting mixture refrigerated for 60 h, a colourless precipitatebeing formed. The solid was collected by filtration, washed with diethylether (2×300 ml) and vacuum dried at 30° C. to give morphiliniumdimorhpholinoacetate (298 g, 94%) as a colourless solid, which containeda small amount of water.

Mpt. 139-139.5° C. ¹H NMR (300 MHz, CDCl₃) δ: 2.83 (12H, br m), 3.26(1H, s), 3.78 (12H, br m), 7.78 (2H, br s). Microanalysis Calculated %C, 52.93; H, 8.58; N, 13.24; water: 0.1%. found C, 52.84; H, 8.84; N,13.15, water: 0.1%.

b)

Using a method based on that described by Kerfanto and Jegou, (Kerfanto,M.; Jegou, D. Compt. Rendus. 1965, 261(11), 2232-2233) morphiliniumdimorpholinoacetate (127 g, 0.40 mol) was added to a stirred solution ofhydrochloric acid (94.3 g, 6.5 mol) in 1-propanol (600 ml) and theresulting mixture heated to 80° C., under reflux, for 2 h. The resultingcolourless suspension was filtered to remove morphiline hydrochloride,and the filtrate fractionally distilled, under reduced pressure, to giveexcess 1-propanol and the colourless oil, propyl 2,2-dipropoxyacetate(57.14 g, 65%).

¹H NMR (300 MHz, CDCl₃) δ: 0.86-1.05 (9H, m), 1.55-1.78 (6H, m),3.47-3.65 (4H, m), 4.15 (2H, t), 4.89 (1H, s).

c)

A mixture of propyl 2,2-dipropoxyacetate (43.66 g, 0.20 mol), acetylchloride (28 ml, 0.394 mol) and iodine (0.25 g, 1.0 mmol) was heated to55° C., under reflux, for 16 h. Since GC analysis showed that somepropyl 2,2-dipropoxyacetate starting material was still present, secondportions of acetyl chloride (14 ml, 0.197 mol) and iodine (0.25 g, 1.0mmol) were added, and heating continued for a further 6 h. The productwas then purified by fractional distillation under reduced pressure togive (S/R)-propyl 2-chloro-2-propoxyacetate (32.67 g, 84%) as a paleorange oil (trace of iodine present).

Bpt. 116-119.5° C./approx. 10 mmHg. ¹H NMR (300 MHz, CDCl₃) δ: 0.97 (3H,t), 0.98 (3H, t), 1.63-1.82 (4H, m), 3.58 (1H, dt), 3.93 (1H, dt),4.13-4.26 (2H, m), 5.83 (1H, s).

d)

Triethylphosphite (27 ml, 0.155 mol) was added to (S/R)-propyl2-chloro-2-propoxyacetate (29.21 g, 0.15 mol), resulting in an immediatedecolourisation of the pale orange acetate, and the resulting mixtureheated to 140° C., under reflux, for 6 h, a colourless gas beingevolved. The mixture was then fractionally distilled under reducedpressure to give the product, (S/R)-propyl2-(diethoxyphosphoryl)-2-propoxyacetate (35.78 g, 80%) as a colourlessoil.

Bpt. 155-160° C./approx. 3 mmHg. ¹H NMR (300 MHz, CDCl₃) δ: 0.95 (3H,t), 0.98 (3H, t), 1.31-1.39 (6H, m), 1.60-1.76 (4H, m), 3.49 (1H, dt),3.62 (1H, dt), 4.12-4.30 (6H, m), 4.31 (1H, d, J_(HP)=19 Hz).

e)

A THF (50 ml) solution of (S/R)-propyl2-(diethoxyphosphoryl)-2-propoxyacetate (18.52 g, 62.5 mmol) was addeddropwise, at 0° C., to a stirred suspension of sodium hydride (60%dispersion in mineral oil, 2.50 g, 62.5 mmol) in THF (50 ml), and theresulting mixture stirred for 30 min. A THF (100 ml) solution of4-benzyloxybenzaldehyde (10.62 g, 50.0 mmol) was added, the resultingsolution allowed to warm to room temperature, and stirring continued for24 h. TLC showed a considerable amount of unreacted4-benzyloxybenzaldehyde was still present so a further portion of sodiumhydride (60% dispersion in mineral oil, 1.0 g, 25.0 mmol) was added andstirring continued for a further 18 h. The mixture was carefully dilutedwith 0.5N HCl (400 ml), the products extracted into ethyl acetate (3×200ml), and the combined organic phases washed with brine, dried (MgSO₄)and evaporated to give a yellow gum, which was purified by columnchromatography on silica gel (10% ethyl acetate in n-heptane eluent) togive the intermediate, (E/Z)-propyl3-(4-benzyloxyphenyl)-2-propoxy-acrylate as a colourless gum.

The (E/Z)-propyl 3-(4-benzyloxyphenyl)-2-propoxy-acrylate was dissolvedin ethanol (200 ml), palladium on activated charcoal (10 wt. %, 2.18 g,2.05 mmol) added and the mixture hydrogenated at 30 lb/in² H₂ pressurefor 20 h. The catalyst was removed by filtration through celite and thesolvent evaporated to give an orange gum, which contained both thepropyl and the ethyl (formed by trans-esterification) esters of(S/R)-3-(4-hydroxyphenyl)-2-propoxy-propionic acid. These were separatedby column chromatography on silica gel (15% ethyl acetate in n-heptaneeluent) to give, in respective order of elution, (S/R)-propyl3-(4-hydroxyphenyl)-2-propoxy-propionate (4.52 g, 41%) and a mixture ofboth (S/R)-propyl and (S/R)-ethyl3-(4-hydroxyphenyl)-2-propoxy-propionates (4.98 g, approx. 45%) ascolourless oils.

(S/R)-propyl 3-(4-hydroxyphenyl)-2-propoxy-propionate: ¹H NMR (300 MHz,CDCl₃) δ: 0.84 (3H, t), 0.90 (3H, t), 1.48-1.69 (4H, m), 2.95 (2H, d),3.25 (1H, dt), 3.52 (1H, dt), 4.00 (1H, t), 4.07 (2H, t), 6.43 (1H, brs), 6.74 (2H, dm), 7.07 (2H, dm). ¹³C NMR (75 MHz, CDCl₃) δ: 10.2 (q),10.3 (q), 21.8 (t), 22.7 (t), 38.4 (t), 66.6 (t), 72.5 (t), 80.6 (d),115.2 (d), 128.5 (s), 130.4 (d), 154.7 (s), 173.2 (s). MS: 266 (M⁺), 206(M−PrOH), 179, 164, 137, 107 (100%).

f)

The title compound (350 mg, 74%) was prepared as a colourless gum from(S/R)-propyl 3-(4-hydroxyphenyl)-2-propoxy-propionate (280 mg, 1.05mmol) and (E)-3-biphenyl-4-yl-but-2-en-1-ol (224 mg, 1.0 mmol) by aprocedure analogous to that described in example 52c.

¹H NMR (300 MHz, CDCl₃) δ: 0.85 (3H, t), 0.90 (3H, t), 1.49-1.69 (4H,m), 2.17 (3H, d), 3.91-3.02 (2H, m), 3.23 (1H, dt), 3.52 (1H, dt), 3.97(1H, dd), 4.07 (2H, t), 4.74 (2H, d), 6.11 (1H, tm), 6.88 (2H, dm), 7.17(2H, dm), 7.30-7.38 (1H, m), 7.40-7.63 (8H, m). LCMS: 679 (M+207), 495(100%, M+Na), 490 (M+NH₄), 207.

Example 144

(E)-(S/R)-3-[4-(3-Biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-propoxy-propionicacid

The title compound was prepared from (E)-(S/R)-propyl3-[4-(3-biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-propoxy-propionate(example 143) (330 mg, 0.70 mmol) and sodium hydroxide (1M, 1.4 ml, 1.4mmol) by a procedure analogous to that described in example 51, yielding(E)-(S/R)-3-[4-(3-biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-propoxy-propionicacid (300 mg, 100%) as a colourless gum.

¹H NMR (300 MHz, CDCl₃) δ: 0.88 (3H, t), 1.58 (2H, sextet), 2.17 (3H,s), 2.96 (1H, dd), 3.10 (1H, dd), 3.37 (1H, dt), 3.50 (1H, dt), 4.06(1H, dd), 4.75 (2H, d), 6.11 (1H, t), 6.90 (2H, dm), 7.17 (2H, dm),7.30-7.38 (1H, m), 7.40-7.63 (8H, m), carboxylic acid proton notobserved. LCMS: 637 (M+207), 453 (100%, M+Na), 207.

Example 145

(E)-(S)-3-{4-[3-(3,5-Diethoxyoxy-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionicacid ethyl ester

The title compound was prepared from 3,5-dihydroxybenzaldehyde (3.0 g,22.0 mmol) and ethyl iodide (17.2 g, 110 mmol) by a sequence analogousto that described in example 75.

¹H NMR (300 MHz, CDCl₃) δ: 1.15 (t, 3H), 1.20 (t, 3H), 1.38 (t, 6H),2.95 (d, 2H), 3.30-3.40 (m, 1H), 3.53-3.65 (m, 1H), 3.98 (q, 4H), 4.15(q, 2H), 4.63 (d, 2H), 6.28-6.40 (m, 2H), 6.53 (d, 2H), 6.60 (d, 1H),6.87 (d, 2H), 7.15 (d, 2H).

Example 146

(E)-(S)-3-{4-[3-(3,5-Diethoxyoxy-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionicacid

The title compound was prepared from(E)-(S)-3-{4-[3-(3,5-diethoxyoxy-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionicacid ethyl ester (730 mg, 1.6 mmol) by a procedure analogous to thatdescribed in example 26.

¹H NMR (300 MHz, CDCl₃) δ: 1.15 (t, 3H), 1.22 (t, 3H), 1.38 (t, 6H),2.95 (d, 2H), 3.28-3.38 (m, 1H), 3.53-3.65 (m, 1H), 3.98 (q, 4H), 4.15(q, 2H), 4.63 (d, 2H), 6.28-6.40 (m, 2H), 6.53 (d, 2H), 6.60 (d, 1H),6.85 (d, 2H), 7.15 (d, 2H).

Example 147

(E)-(S)-3-{4-[3-(3,5-Bis-trifluoromethyl-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionicacid ethyl ester

The title compound was prepared from3,5-bis(trifluoromethyl)benzaldehyde (5.0 g, 20.7 mmol) by a sequenceanalogous to that described in example 23. The title compound waspurified on HPLC, using ethyl acetate/heptane (20:80) as eluent.

¹H NMR (300 MHz, CDCl₃) δ: 1.15 (t, 3H), 1.22 (t, 3H), 2.97 (d, 2H),3.30-3.42 (m, 1H), 3.55-3.67 (m, 1H), 3.98 (t, 1H), 4.18 (q, 2H), 4.72(d, 2H), 6.55 (dt, 1H), 6.80 (d, 1H), 6.89 (d, 2H), 7.18 (d, 2H), 7.75(bs, 1H), 7.82 (bs, 2H).

Example 148

(E)-(S)-3-{4-[3-(3,5-Bis-trifluoromethyl-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionicacid

The title compound was prepared from(E)-(S)-3-{4-[3-(3,5-bis-trifluoromethyl-phenyl)-allyloxy]-phenyl}-2-ethoxy-propionicacid ethyl ester (0.58 g, 1.2 mmol) by a procedure analogous to thatdescribed in example 26.

¹H NMR (300 MHz, CDCl₃) δ: 1.18 (t, 3H), 2.98 (dd, 1H), 3.08 (dd, 1H),3.36-3.48 (m, 1H), 3.58-3.71 (m, 1H), 4.05 (dd, 1H), 4.72 (d, 2H), 6.55(dt, 1H), 6.80 (d, 1H), 6.89 (d, 2H), 7.20 (d, 2H), 7.75 (bs, 1H), 7.82(bs, 2H).

Example 149

(E)-(R,S)-3-[4-(3-Biphenyl-4-yl-allyloxy)-phenyl]-2-ethoxy-propionicacid ethyl ester

The title compound was prepared from 3-biphenyl-4-yl-prop-2-en-1-ol(0.25 g, 0.001 mol) by a procedure analogous to that described inexample 3c yielding 0.050 g of(E)-(R,S)-3-[4-(3-biphenyl-4-yl-allyloxy)-phenyl]-2-ethoxy-propionicacid ethyl ester.

¹H NMR (200 MHz, CDCl₃) δ: 1.1-1.26 (6H, m), 2.97 (2H, d), 3.3-3.4 (1H,m), 3.52-3.7 (1H, m), 4.0 (1H, t), 4.15 (2H, q), 4.75 (2H, dd), 6.35-6.5(1H, dt), 6.75 (1H, d), 6.87 (2H, d), 7.15 (2H, d), 7.4-7.7 (9H, m).

Example 150

(E)-(R,S)-3-[4-(3-Biphenyl-4-yl-allyloxy)-phenyl]-2-ethoxy-propionicacid

The title compound was prepared from(E)-(S)-3-[4-(3-biphenyl-4-yl-allyloxy)-phenyl]-2-ethoxy-propionic acidethyl ester (example 149) (0.040 g) by a procedure analogous to thatdescribed in example 2 yielding 0.0045 g of(E)-(R,S)-3-[4-(3-biphenyl-4-yl-allyloxy)-phenyl]-2-ethoxy-propionicacid.

¹H NMR (300 MHz, CDCl₃) δ: 1.14 (3H, t), 2.85 (1H, dd), 3.1 (1H, dd)3.42-3.57 (2H, m), 3.84-3.96 (2H, m), 4.1 (1H, dd), 4.7 (2H, d), 6.3-6.5(1H, dt), 6.78 (1H, d), 6.88 (2H, d), 7.15 (2H, d) 7.4-7.6 (9H, m).

Example 151

(E)-(S)-4-(3-{3-[4-(2-Ethoxy-2-ethoxycarbonyl-ethyl)-phenoxy]-propenyl}-phenoxymethyl)-benzoicacid methyl ester

a)

(E)-3-(3-Hydroxy-propenyl)-phenol was prepared from3-hydroxybenzaldehyde (6.0 g, 0.049 mol) by a procedure analogous tothat described in example 1a-b yielding 1.5 g

¹H NMR (300 MHz, CDCl₃) δ: 1.4 (1H, t), 4.27 (2H, m), 4.88 (1H, s), 6.35(1H, dt), 6.57 (1H, d), 6.68 (1H, dd), 6.87 (1H, s), 6.96 (1H, d), 7.19(1H, dd).

b)

A mixture of (E)-3-(3-Hydroxy-propenyl)-phenol (0.5 g, 3.33 mmol),methyl 4-(bromomethyl) benzoate (763 mg, 3.33 mmol) and potassiumcarbonate (1.8 g, 13.3 mmol) in acetone (40 ml) was stirred at roomtemperature over night. The reaction mixtyre was added water (30 ml) andacidified with 1N HCl and extracted with ethyl acetate (90 ml). Theorganic phase was washed with water, brine and dried with sodiumsulphate and evaporated and dried in vacuo yielding 954 mg (96%)(E)-4-[3-(3-Hydroxy-propenyl)-phenoxymethyl]-benzoic acid methyl ester.

¹H NMR (300 MHz, CDCl₃) δ: 3.8 (3H, s), 4.24 (2H, d), 5.15 (2H, s), 6.3(1H, dt), 6.57 (1H, d), 7.0 (2H, d), 7.2 (1H, d), 7.51 (2H, d), 8.08(2H, d).

c)

The title compound was prepared from(E)-4-[3-(3-Hydroxy-propenyl)-phenoxymethyl]-benzoic acid methyl ester(0.298 g, 1.0 mmol) by a procedure analogous to that described inexample 3c yielding 0.184 g (35%) of(E)-(S)-4-(3-{3-[4-(2-Ethoxy-2-ethoxycarbonyl-ethyl)-phenoxy]-propenyl}-phenoxymethyl)-benzoicacid methyl ester.

¹H NMR (300 MHz, CDCl₃) δ: 1.15-1.35 (6H, m), 2.9 (2H, d) 3.3-3.45 (1H,m), 3.53-3.68 (1H, m), 3.89 (3H, s), 3.97 (1H, t), 4.13 (2H, q), 4.68(2H, dd), 5.15 (2H, s), 6.35 (1H, dt), 6.62 (1H, d), 6.87 (3H, d), 7.05(2H, d), 7.13-7.3 (3H, m), 7.5 (2H, d), 8.10 (2H, d).

Example 152

(E)-(S)-4-(3-{3-[4-(2-Carboxy-2-ethoxy-ethyl)-phenoxy]-propenyl}-phenoxymethyl)-benzoicacid

The title compound was prepared from(E)-(S)-4-(3-{3-[4-(2-ethoxy-2-ethoxycarbonyl-ethyl)-phenoxy]-propenyl}-phenoxymethyl)-benzoicacid methyl ester (example 151) (0.220 g) by a procedure analogous tothat described in example 2 yielding 0.160 g (77%)(E)-(S)-4-(3-{3-[4-(2-carboxy-2-ethoxy-ethyl)-phenoxy]-propenyl}-phenoxymethyl)-benzoicacid.

¹H NMR (300 MHz, CDCl₃) δ: δ: 1.17 (3H, t), 2.9-3.15 (2H, m) 3.3-3.68(2H, m), 4.1 (2H, q), 4.67 (2H, d), 5.17 (2H, s), 6.35 (1H, dt), 6.68(1H, d), 6.86 (3H, d), 7.05 (2H, d), 7.12-7.32 (3H, m), 7.52 (2H, d),8.12 (2H, d).

Example 153

(E)-(S)-Ethyl2-Ethoxy-3-{4-[3-(4′-fluoro-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionate

a)

The colourless solid (E)-ethyl 3-(4′-fluoro-biphenyl-4-yl)-but-2-enoatewas prepared from (E)-ethyl 3-(4-iodophenyl)-but-2-enoate (example 91 a)and 4-fluorobenzene boronic acid by a procedure analogous to thatdescribed in example 52a.

Mpt. 63.5-64.5° C. ¹H NMR (300 MHz, CDCl₃) δ: 1.33 (3H, t), 2.61 (3H,d), 4.23 (2H, q), 6.20 (1H, m), 7.14 (2H, dd), 7.52-7.62 (6H, m). MS:284 (100%, M⁺), 255, 239, 212, 196. Microanalysis Calculated % C, 76.04;H, 6.03. found C, 76.10; H, 6.17.

b)

The colourless solid (E)-3-(4′-fluoro-biphenyl-4-yl)-but-2-en-1-ol wasprepared by DIBAL-H reduction of (E)-ethyl3-(4′-fluoro-biphenyl-4-yl)-but-2-enoate as described for example 52b.

Mpt. 120.5-122° C. (n-heptane). ¹H NMR (300 MHz, CDCl₃) δ: 1.39 (1H, brs), 2.12 (3H, d), 4.40 (2H, d), 6.05 (1H, tm), 7.12 (2H, dd), 7.42-7.60(6H, m). MS: 242 (100%, M⁺), 227 (M-Me), 224 (M−H₂O), 203, 199.Microanalysis Calculated % C, 79.32; H, 6.24. found C, 79.34; H, 6.37.

c)

The title compound (849 mg, 89%) was prepared as a colourless gum from(E)-3-(4′-fluorobiphenyl-4-yl)-but-2-en-1-ol (500 mg, 2.06 mmol) and(S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (516 mg, 2.17 mmol) bya procedure analogous to that described in example 52c.

¹H NMR (200 MHz, CDCl₃) δ: 1.17 (3H, t), 1.23 (3H, t), 2.17 (3H, d),2.97 (2H, d), 3.27-3.44 (1H, m), 3.52-3.69 (1H, m), 3.98 (1H, t), 4.17(2H, q), 4.75 (2H, d), 6.12 (1H, tm), 6.88 (2H, dm), 7.05-7.22 (4H, m),7.44-7.62 (6H, m). LCMS: 687 (M+225), 641 (687-EtOH), 485 (M+Na), 480(M+NH₄), 225 (100%).

Example 154

(E)-(S)-2-Ethoxy-3-{4-[3-(4′-fluoro-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionicacid

The title compound was prepared from (E)-(S)-ethyl2-ethoxy-3-{4-[3-(4′-fluoro-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionate(example 153) (463 mg, 1.0 mmol) and sodium hydroxide (1M, 1.5 ml, 1.5mmol) by a procedure analogous to that described in example 51, yielding(E)-(S)-2-ethoxy-3-{4-[3-(4′-fluoro-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionicacid (229 mg, 53%) as a colourless solid containing a trace of water.

¹H NMR (300 MHz, CDCl₃) δ: 1.19 (3H, t), 2.16 (3H, d), 2.97 (1H, dd),3.09 (1H, dd), 3.42-3.65 (2H, m), 4.07 (1H, dd), 4.75 (2H, d), 6.11 (1H,tm), 6.90 (2H, dm), 7.07-7.20 (4H, m), 7.45-7.60 (6H, m), carboxylicacid proton not observed. LCMS: 457 (M+Na), 225 (100%). Microanalysisfor C₂₇H₂₇FO₄.0.05H₂O Calculated % C, 74.48; H, 6.27; H₂O 0.21. found C,74.25; H, 6.39; H₂O, 0.21.

Example 155

(E)-(S)-Ethyl2-Ethoxy-3-{4-[3-(4-Iodophenyl)-but-2-enyloxy]-phenyl}-propionate

The title compound (398 mg, 80%) was prepared as a colourless gum, from(E)-3-(4-iodophenyl)-but-2-en-1-ol (example 107a) (275 mg, 1.0 mmol) and(S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (256 mg, 1.07 mmol) bya procedure analogous to that described in example 52c.

¹H NMR (300 MHz, CDCl₃) δ: 1.17 (3H, t), 2.10 (3H, d), 2.96 (2H, d),3.30-3.40 (1H, m), 3.55-3.65 (1H, m), 3.97 (1H, t), 4.16 (2H, q), 4.70(2H, d), 6.04 (1H, tm), 6.86 (2H, dm), 7.13-7.20 (4H, m), 7.64 (2H, dm).LCMS: 751 (M+257), 705 (751-EtOH), 517 (100%, M+Na), 512 (M+NH₄), 449(M+H-EtOH), 257, 130.

1. A compound of formula (I)

wherein A is heteroaryl, a 5-10 membered ring system containing from 1-4heteroatoms selected from O, N, and S, and wherein A is optionallysubstituted with one or more substituents selected from hydroxy,halogen, perhalomethyl, perhalomethoxy, acyl, cyano, amino,C₁₋₆-alkylamino, C₁₋₆-dialkylamino, methylenedioxy, aralkenyl,aralkynyl, heteroaryloxy, heteroaralkoxy, aralkyl, heteroaralkyl, astraight or branched saturated carbon chain containing from 1-6 carbonssubstituted with 1 heteroaryl group, arylamino, or A is optionallysubstituted with C₁₋₆-alkyl, C₂₋₆-alkenyl or C₂₋₆-alkynyl each of whichis optionally substituted with one or more substituents selected fromC₁₋₆-alkoxycarbonyl or carboxy, or A is optionally substituted withC₁₋₆-alkoxy, C₁₋₆-alkylthio or C₂₋₆-alkenyloxy each of which isoptionally substituted with one or more halogens, or A is optionallysubstituted with aryloxy, arylthio or aralkoxy each of which isoptionally substituted with one or more substituents selected fromC₁₋₆-alkoxy, nitro, carboxy or C₁₋₆-alkoxycarbonyl; and X₁ and X₂independently are hydrogen, aryl or heteroaryl, a 5-10 membered ringsystem containing from 1-4 heteroatoms selected from O, N, and S, eachof which is optionally substituted with one or more substituentsselected from hydroxy, aryloxy, arylthio, aralkoxy, heteroaryloxy,aralkoxy, C₁₋₆-alkoxy, C₁₋₆-alkylthio, halogen, perhalomethyl,perhalomethoxy, acyl, aryl, heteroaryl, aralkyl, heteroaralkyl, astraight or branched saturated carbon chain containing from 1-6 carbonssubstituted with 1 heteroaryl group, cyano, amino, C₁₋₆-alkylamino,C₁₋₆-dialkylamino, arylamino or methylenedioxy, or aryl or heteroaryleach of which is optionally substituted with one or more substituentsselected from C₁₋₆-alkyl, C₂₋₆-alkenyl or C₂₋₆-alkynyl each of which isoptionally substituted with hydroxy; and Y is hydrogen, or Y isC₁₋₁₂-alkyl, C₂₋₁₂-alkenyl, C₂₋₁₂-alkynyl, C₄₋₁₂-alkenynyl, aralkyl orheteroaralkyl each of which is optionally substituted with one or moresubstituents selected from halogen, C₁₋₆-alkyl, perhalomethyl, hydroxy,aryl, heteroaryl, a 5-10 membered ring system containing from 1-4heteroatoms selected from O, N, and S, carboxy or amino; and Z ishydrogen, halogen, hydroxy, or Z is C₁₋₆-alkyl or C₁₋₆-alkoxy each ofwhich is optionally substituted with one or more substituents selectedfrom halogen, hydroxy, carboxy, amino, cyano or C₁₋₆-alkoxy; and Q is O,S or NR₆, wherein R₆ is hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl, C₄₋₆-alkenynyl, aralkyl, heteroaralkyl and wherein R₆ isoptionally substituted with one or more substituents selected fromhalogen, hydroxy, C₁₋₆-alkoxy, amino or carboxy; and Ar is arylene,which can be optionally substituted with one or more substituentsselected from C₁₋₆-alkyl, aryl or C₁₋₆-alkoxy each of which can beoptionally substituted with halogen, hydroxy, carboxy, cyano orheterocyclyl; and R₁ is hydrogen, hydroxy or halogen; or R₁ forms a bondtogether with R₂; and R₂ is hydrogen or C₁₋₆-alkyl; or R₂ forms a bondtogether with R₁; and R₃ is hydrogen, or R₃ is C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl, C₄₋₆-alkenynyl, aryl, aralkyl, C₁₋₆-alkoxyC₁₋₆-alkyl,acyl, heterocyclyl, a 5-10 membered ring system containing from 1-4heteroatoms selected from O, N, and S, heteroaryl, a 5-10 membered ringsystem containing from 1-4 heteroatoms selected from O, N, and S, orheteroaralkyl, a straight or branched saturated carbon chain containingfrom 1-6 carbons substituted with 1 heteroaryl group, each of which isoptionally substituted with one or more substituents selected fromhalogen, perhalomethyl, hydroxy or cyano; and R₄ is hydrogen,C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₄₋₆-alkenynyl or aryl; and n isan integer ranging from 0 to 3; and m is an integer ranging from 0 to 1;or a pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate thereof, or any tautomeric forms, stereoisomers,mixture of stereoisomers, or a racemic mixture.
 2. A compound accordingto claim 1 of formula (I)

wherein A is aryl or heteroaryl and wherein A is optionally substitutedwith one or more substituents selected from hydroxy, halogen,perhalomethyl, perhalomethoxy, acyl, cyano, amino, C₁₋₆-alkylamino,C₁₋₆-dialkylamino, methylenedioxy, aralkenyl, aralkynyl, heteroaryloxy,heteroaralkoxy, aralkyl, heteroaralkyl, arylamino, or A is optionallysubstituted with C₁₋₆-alkyl, C₂₋₆-alkenyl or C₂₋₆-alkynyl each of whichis optionally substituted with one or more substituents selected fromC₁₋₆-alkoxycarbonyl or carboxy, or A is optionally substituted withC₁₋₆-alkoxy, C₁₋₆-alkylthio or C₂₋₆-alkenyloxy each of which isoptionally substituted with one or more halogens, or A is optionallysubstituted with aryloxy, arylthio or aralkoxy each of which isoptionally substituted with one or more substituents selected fromC₁₋₆-alkoxy, nitro, carboxy or C₁₋₆-alkoxycarbonyl; and X₁ and X₂independently are hydrogen, aryl or heteroaryl each of which isoptionally substituted with one or more substituents selected fromhydroxy, aryloxy, arylthio, aralkoxy, heteroaryloxy, aralkoxy,C₁₋₆-alkoxy, C₁₋₆-alkylthio, halogen, perhalomethyl, perhalomethoxy,acyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cyano, amino,C₁₋₆-alkylamino, C₁₋₆-dialkylamino, arylamino or methylenedioxy, or arylor heteroaryl each of which is optionally substituted with one or moresubstituents selected from C₁₋₆-alkyl, C₂₋₆-alkenyl or C₂₋₆-alkynyl eachof which is optionally substituted with hydroxy; and Y is hydrogen, or Yis C₁₋₁₂-alkyl, C₂₋₁₂-alkenyl, C₂₋₁₂-alkynyl, C₄₋₁₂-alkenynyl, aralkylor heteroaralkyl each of which is optionally substituted with one ormore substituents selected from halogen, C₁₋₆-alkyl, perhalomethyl,hydroxy, aryl, heteroaryl, carboxy or amino; and Z is hydrogen, halogen,hydroxy, or Z is C₁₋₆-alkyl or C₁₋₆-alkoxy each of which is optionallysubstituted with one or more substituents selected from halogen,hydroxy, carboxy, amino, cyano or C₁₋₆-alkoxy; and Q is O, S or NR₆,wherein R₆ is hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₄₋₆-alkenynyl, aralkyl, heteroaralkyl and wherein R₆ is optionallysubstituted with one or more substituents selected from halogen,hydroxy, C₁₋₆-alkoxy, amino or carboxy; and Ar is arylene, which can beoptionally substituted with one or more substituents selected fromC₁₋₆-alkyl, aryl or C₁₋₆-alkoxy each of which can be optionallysubstituted with halogen, hydroxy, carboxy, cyano or heterocyclyl; andR₁ is hydrogen, hydroxy or halogen; or R₁ forms a bond together with R₂;and R₂ is hydrogen or C₁₋₆-alkyl; or R₂ forms a bond together with R₁;and R₃ is hydrogen, or R₃ is C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₄₋₆-alkenynyl, aryl, aralkyl, C₁₋₆-alkoxyC₁₋₆-alkyl, acyl,heterocyclyl, heteroaryl or heteroaralkyl each of which is optionallysubstituted with one or more substituents selected from halogen,perhalomethyl, hydroxy or cyano; and R₄ is hydrogen, C₁₋₆-alkyl,C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₄₋₆-alkenynyl or aryl; and n is an integerranging from 1 to 3; and m is 1; or a pharmaceutically acceptable saltthereof, or a pharmaceutically acceptable solvate thereof, or anytautomeric forms, stereoisomers, mixture of stereoisomers, or a racemicmixture.
 3. A compound according to claim 1 of formula (I)

wherein A is heteroaryl and wherein A is optionally substituted with oneor more substituents selected from C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl, hydroxy, aryloxy, arylthio, aralkoxy, C₁₋₆-alkoxy,C₁₋₆-alkylthio, heteroaryloxy, heteroaralkoxy, halogen, perhalomethyl,perhalomethoxy, acyl, aralkyl, heteroaralkyl, cyano, amino,C₁₋₆-alkylamino, C₁₋₆-dialkylamino, arylamino or methylenedioxy; and X₁and X₂ independently are hydrogen, aryl or heteroaryl optionallysubstituted with one or more substituents selected from C₁₋₆-alkyl,C₂₋₆-alkenyl, C₂₋₆-alkynyl, hydroxy, aryloxy, arylthio, aralkoxy,heteroaryloxy, aralkoxy, C₁₋₆-alkoxy, C₁₋₆-alkylthio, halogen,perhalomethyl, perhalomethoxy, acyl, aryl, heteroaryl, aralkyl,heteroaralkyl, cyano, amino, C₁₋₆-alkylamino, C₁₋₆-dialkylamino,arylamino or methylenedioxy; Y is hydrogen, C₁₋₁₂-alkyl, C₂₋₁₂-alkenyl,C₂₋₁₂-alkynyl, C₄₋₁₂-alkenynyl, aralkyl or heteroaralkyl optionallysubstituted with one or more substituents selected from halogen,C₁₋₆-alkyl, perhalomethyl, hydroxy, aryl, heteroaryl, carboxy or amino;and Z is hydrogen, halogen, hydroxy, C₁₋₆-alkyl or C₁₋₆-alkoxyoptionally substituted with one or more substituents selected fromhalogen, hydroxy, carboxy, amino, cyano or C₁₋₆-alkoxy; and Q is O, S orNR₆, wherein R₆ is hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₄₋₆-alkenynyl, aralkyl, heteroaralkyl and wherein R₆ is optionallysubstituted with one or more substituents selected from halogen,hydroxy, C₁₋₆-alkoxy, amino or carboxy; and Ar is arylene, which can beoptionally substituted with one or more substituents selected fromC₁₋₆-alkyl, aryl or C₁₋₆-alkoxy each of which can be optionallysubstituted with halogen, hydroxy, carboxy, cyano or heterocyclyl; andR₁ is hydrogen, hydroxy or halogen; or R₁ forms a bond together with R₂;and R₂ is hydrogen or C₁₋₆-alkyl; or R₂ forms a bond together with R₁;and R₃ is hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₄₋₆-alkenynyl, aryl, aralkyl, C₁₋₆-alkoxyC₁₋₆-alkyl, acyl,heterocyclyl, heteroaryl or heteroaralkyl groups optionally substitutedwith one or more substituents selected from halogen, perhalomethyl,hydroxy or cyano; and R₄ is hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl, C₄₋₆-alkenynyl or aryl; and n is an integer ranging from 0to 3; and m is an integer ranging from 0 to 1; or a pharmaceuticallyacceptable salt thereof, or a pharmaceutically acceptable solvatethereof, or any tautomeric forms, stereoisomers, mixture ofstereoisomers, or a racemic mixture.
 4. A compound according to claim 1of formula (I)

wherein A is heteroaryl and wherein A is optionally substituted with oneor more substituents selected from C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl, hydroxy, aryloxy, arylthio, aralkoxy, C₁₋₆-alkoxy,C₁₋₆-alkylthio, heteroaryloxy, heteroaralkoxy, halogen, perhalomethyl,perhalomethoxy, acyl, aralkyl, heteroaralkyl, cyano, amino,C₁₋₆-alkylamino, C₁₋₆-dialkylamino, arylamino or methylenedioxy; and X₁and X₂ independently are hydrogen, aryl or heteroaryl optionallysubstituted with one or more substituents selected from C₁₋₆-alkyl,C₂₋₆-alkenyl, C₂₋₆-alkynyl, hydroxy, aryloxy, arylthio, aralkoxy,heteroaryloxy, aralkoxy, C₁₋₆-alkoxy, C₁₋₆-alkylthio, halogen,perhalomethyl, perhalomethoxy, acyl, aryl, heteroaryl, aralkyl,heteroaralkyl, cyano, amino, C₁₋₆-alkylamino, C₁₋₆-dialkylamino,arylamino or methylenedioxy; and Y is hydrogen, C₁₋₁₂-alkyl,C₂₋₁₂-alkenyl, C₂₋₁₂-alkynyl, C₄₋₁₂-alkenynyl, aralkyl or heteroaralkyloptionally substituted with one or more substituents selected fromhalogen, C₁₋₆-alkyl, perhalomethyl, hydroxy, aryl, heteroaryl, carboxyor amino; and Z is hydrogen, halogen, hydroxy, C₁₋₆-alkyl or C₁₋₆-alkoxyoptionally substituted with one or more substituents selected fromhalogen, hydroxy, carboxy, amino, cyano or C₁₋₆-alkoxy; and Q is O, S orNR₆, wherein R₆ is hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₄₋₆-alkenynyl, aralkyl, heteroaralkyl and wherein R₆ is optionallysubstituted with one or more substituents selected from halogen,hydroxy, C₁₋₆-alkoxy, amino or carboxy; and Ar is arylene, of which canbe optionally substituted with one or more substituents selected fromC₁₋₆-alkyl, aryl or C₁₋₆-alkoxy each of which can be optionallysubstituted with halogen, hydroxy, carboxy, cyano or heterocyclyl; andR₁ is hydrogen, hydroxy or halogen; or R₁ forms a bond together with R₂;and R₂ is hydrogen or C₁₋₆-alkyl; or R₂ forms a bond together with R₁;and R₃ is hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₄₋₆-alkenynyl, aryl, aralkyl, C₁₋₆-alkoxyC₁₋₆-alkyl, acyl,heterocyclyl, heteroaryl or heteroaralkyl groups optionally substitutedwith one or more substituents selected from halogen, perhalomethyl,hydroxy or cyano; and R₄ is hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl, C₄₋₆-alkenynyl or aryl; and n is an integer ranging from 0to 3; and m is an integer ranging from 0 to 1; or a pharmaceuticallyacceptable salt thereof, or a pharmaceutically acceptable solvatethereof, or any tautomeric forms, stereoisomers, mixture ofstereoisomers, or a racemic mixture.
 5. A compound according to claim 1,wherein A is heteroaryl optionally substituted with one or moresubstituents selected from from C₁₋₆-alkyl, C₂₋₆-alkenyl each of whichis optionally substituted with one or more substituents selected fromC₁₋₆-alkoxycarbonyl or carboxy, or A is optionally substituted witharyloxy optionally substituted with one or more C₁₋₆-alkoxy, or A isoptionally substituted with aralkoxy optionally substituted with one ormore substituents selected from C₁₋₆-alkoxy, nitro, carboxy orC₁₋₆-alkoxycarbonyl, or A is optionally substituted with C₁₋₆-alkoxyoptionally substituted with one or more halogens, or A is optionallysubstituted with aralkenyl, C₂₋₆-alkenyloxy, aralkynyl, halogen,perhalomethyl, perhalomethoxy, acyl, aralkyl or methylenedioxy.
 6. Acompound according to claim 1, wherein A is heteroaryl optionallysubstituted with one or more substituents selected from aryloxy,arylthio, aralkoxy, C₁₋₆-alkoxy, C₁₋₆-alkylthio, halogen, perhalomethyl,aralkyl, heteroaralkyl, heteroaryloxy or heteroaralkoxy.
 7. A compoundaccording to claim 1, wherein A is heteroaryl optionally substitutedwith one or more substituents selected from aryloxy, arylthio, aralkoxy,C₁₋₆-alkoxy, C₁₋₆-alkylthio, halogen, perhalomethyl, aralkyl,heteroaralkyl, heteroaryloxy or heteroaralkoxy.
 8. A compound accordingto claim 1, wherein A is heteroaryl.
 9. A compound according to claim 1,wherein X₁ and X₂ independently are hydrogen, aryl or heteroaryloptionally substituted with one or more substituents selected fromaryloxy, arylthio, aralkoxy, halogen, perhalomethyl, aryl, heteroaryl,aralkyl, heteroaralkyl, heteroaryloxy or heteroaralkoxy.
 10. A compoundaccording to claim 9, wherein X₁ and X₂ independently are hydrogen, arylor heteroaryl optionally substituted with one or more substituentsselected from halogen, acyl, aryl, or aryl or heteroaryl optionallysubstituted with one or more substituents selected from C₁₋₆-alkyl,C₂₋₆-alkynyl each of which is optionally substituted with hydroxy.
 11. Acompound according to claim 1, wherein Y is hydrogen or C₁₋₁₂-alkyl. 12.A compound according to claim 1, wherein Z is hydrogen or C₁₋₆-alkoxy.13. A compound according to claim 1, wherein Q is O.
 14. A compoundaccording to claim 1, wherein Ar is arylene optionally substituted withone or more substituents selected from C₁₋₆-alkyl or C₁₋₆-alkoxy each ofwhich can be optionally substituted with carboxy.
 15. A compoundaccording to claim 1, wherein R₁ is hydrogen or R₁ forms a bond togetherwith R₂.
 16. A compound according to claim 1, wherein R₂ is hydrogen.17. A compound according to claim 1, wherein R₃ is C₁₋₆-alkyl oraralkyl.
 18. A compound according to claim 1, wherein R₄ is hydrogen, orC₁₋₃-alkyl.
 19. A compound according to claim 1, wherein alkyl ismethyl, ethyl, n-propyl, iso-propyl, butyl, tert-butyl, pentyl, hexyl,cyclopropyl or cyclopentyl.
 20. A compound according to claim 1, whereinalkenyl is vinyl or 1-propenyl.
 21. A compound according to claim 1,wherein alkynyl is ethynyl, 1-propynyl and 2-propynyl.
 22. A compoundaccording to claim 1, wherein alkoxy is methoxy, ethoxy, propoxy,butoxy, pentoxy, hexoxy, isopropoxy or cyclopentyloxy.
 23. A compoundaccording to claim 1, wherein alkylthio is methylthio, ethylthio,propylthio or cyclopentylthio.
 24. A compound according to claim 1,wherein aryl is phenyl optionally substituted with halogen.
 25. Acompound according to claim 1, wherein arylene is phenylene optionallysubstituted with halogen.
 26. A compound according to claim 1, whereinhalogen is fluorine or chlorine.
 27. A compound according to claim 1,wherein perhalomethyl is trifluoromethyl.
 28. A compound according toclaim 1, wherein acyl is acetyl.
 29. A compound according to claim 1,wherein heteroaryl is furan, thiophene, pyrrole, imidazole, pyrazole,pyridine, quinoline, isoquinoline, quinazoline, quinoxaline, indole,benzimidazole or benzofuran.
 30. A compound according to claim 1,wherein aralkyl is benzyl or phenethyl.
 31. A compound according toclaim 1, wherein aryloxy is phenoxy.
 32. A compound according to claim1, wherein aralkoxy is benzyloxy.
 33. A compound according to claim 1,wherein n is an integer ranging from 1 to 3 and m is
 1. 34. A compoundaccording to claim 1, wherein the substituents Z and Y are arranged in atrans-configuration.
 35. A compound according to claim 1, wherein thesubstituents Z and Y are arranged in a cis-configuration.
 36. Thecompound according to claim 1, which is:(E)-(S)-2-Ethoxy-3-[4-(3-pyridin-2-yl-but-2-enyloxy)-phenyl]-propionicacid ethyl ester,(E)-(S)-2-Ethoxy-3-[4-(3-pyridin-2-yl-but-2-enyloxy)-phenyl]-propionicacid, (S)-3-[4-(2-Benzofuran-3-yl-allyloxy)-phenyl]-2-ethoxy-propionicacid ethyl ester,(S)-3-[4-(2-Benzofuran-3-yl-allyloxy)-phenyl]-2-ethoxy-propionic acid;or a pharmaceutically acceptable salt thereof.
 37. The compoundaccording to claim 4 which is:(E)-(S)-2-Ethoxy-3-[4-(3-pyridin-2-yl-but-2-enyloxy)-phenyl]-propionicacid ethyl ester,(E)-(S)-2-Ethoxy-3-[4-(3-pyridin-2-yl-but-2-enyloxy)-phenyl]-propionicacid, (S)-3-[4-(2-Benzofuran-3-yl-allyloxy)-phenyl]-2-ethoxy-propionicacid ethyl ester,(S)-3-[4-(2-Benzofuran-3-yl-allyloxy)-phenyl]-2-ethoxy-propionic acid;or a pharmaceutically acceptable salt thereof.
 38. The compoundaccording to claim 1, which is:(E)-(S)-3-[4-(3-Benzo[1,3]dioxol-5-yl-allyloxy)-phenyl]-2-ethoxy-propionicacid ethyl ester,(E)-(S)-3-[4-(3-Benzo[1,3]dioxol-5-yl-allyloxy)-phenyl]-2-ethoxy-propionicacid,(E)-(S)-3-[4-(3-Benzofuran-7-yl-allyloxy)-phenyl]-2-ethoxy-propionicacid ethyl ester,(E)-(S)-3-[4-(3-Benzofuran-7-yl-allyloxy)-phenyl]-2-ethoxy-propionicacid, (S)-2-Ethoxy-3-[4-(3-quinolin-2-yl-allyloxy)-phenyl]-propionicacid ethyl ester,(S)-2-Ethoxy-3-[4-(3-quinolin-2-yl-allyloxy)-phenyl]-propionic acid, ora pharmaceutically acceptable salt thereof.
 39. The compound accordingto claim 4 which is:(E)-(S)-3-[4-(3-Benzofuran-7-yl-allyloxy)-phenyl]-2-ethoxy-propionicacid ethyl ester,(E)-(S)-3-[4-(3-Benzofuran-7-yl-allyloxy)-phenyl]-2-ethoxy-propionicacid, (S)-2-Ethoxy-3-[4-(3-quinolin-2-yl-allyloxy)-phenyl]-propionicacid ethyl ester,(S)-2-Ethoxy-3-[4-(3-quinolin-2-yl-allyloxy)-phenyl]-propionic acid, ora pharmaceutically acceptable salt thereof.
 40. The compound accordingto claim 1, which is: (E)-(S)-Ethyl2-Ethoxy-3-{4-[3-(4-furan-2-yl-phenyl)-but-2-enyloxy]-phenyl}-propionate.41. A composition comprising, as an active ingredient, a compoundaccording to claim 1, or a pharmaceutically acceptable salt thereoftogether with a pharmaceutically acceptable carrier or diluent.
 42. Acomposition according to claim 41 in unit dosage form, comprising fromabout 0.05 to about 100 mg of the compound or a pharmaceuticallyacceptable salt thereof.
 43. A composition according to claim 41 fororal, nasal, transdermal, pulmonal, or parenteral administration.
 44. Amethod for the treatment of diabetes and/or obesity, the methodcomprising administering to a subject in need thereof an effectiveamount of a composition according to claim
 41. 45. The method accordingto claim 44, wherein the effective amount of the compound in saidcomposition is in the range of from about 0.05 to about 100 mg per day.46. A composition suitable for treating type I diabetes, type IIdiabetes, impaired glucose tolerance, insulin resistance or obesitycomprising a compound according to claim 1 or a pharmaceuticallyacceptable salt thereof, or a pharmaceutically acceptable solvatethereof, or any tautomeric forms, stereoisomers, mixture ofstereoisomers, or racemic mixture together with one or morepharmaceutically acceptable carriers or diluents and an ACE (angiotensinconverting enzyme) inhibitor.
 47. A method of treating type I diabetes,type II diabetes, impaired glucose tolerance, insulin resistance orobesity comprising administering to a subject in need thereof aneffective amount of a compound according to claim 1 or apharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate thereof, or any tautomeric forms, stereoisomers,mixture of stereoisomers, or racemic mixture, together with one or morepharmaceutically acceptable carriers or diluents and an ACE (angiotensinconverting enzyme) inhibitor to said subject.
 48. A composition suitablefor treating type I diabetes, type II diabetes, impaired glucosetolerance, insulin resistance or obesity comprising a compound accordingto claim 1 or a pharmaceutically acceptable salt thereof, or apharmaceutically acceptable solvate thereof, or any tautomeric forms,stereoisomers, mixture of stereoisomers, or racemic mixture togetherwith one or more pharmaceutically acceptable carriers or diluents and anagent stimulating insulin release from β cells such as a meglitinide,like repaglinide or senaglinide.
 49. A method of treating type Idiabetes, type II diabetes, impaired glucose tolerance, insulinresistance or obesity comprising administering to a subject in needthereof an effective amount of a compound according to claim 1 and anagent stimulating insulin release from β cells such as a meglitinide,like repaglinide or senaglinide, to said subject.
 50. A compositionsuitable for treating type I diabetes, type II diabetes, impairedglucose tolerance, insulin resistance or obesity comprising a compoundaccording to claim 1 or a pharmaceutically acceptable salt thereof, or apharmaceutically acceptable solvate thereof, or any tautomeric forms,stereoisomers, mixture of stereoisomers, or racemic mixture togetherwith one or more pharmaceutically acceptable carriers or diluents and abiguanide like metformin.
 51. A method of treating type I diabetes, typeII diabetes, impaired glucose tolerance, insulin resistance or obesitycomprising administering to a subject in need thereof an effectiveamount of a compound according to claim 1 or a pharmaceuticallyacceptable salt thereof, or a pharmaceutically acceptable solvatethereof, or any tautomeric forms, stereoisomers, mixture ofstereoisomers, or racemic mixture together with one or morepharmaceutically acceptable carriers or diluents and a biguanide, likemetformin, to said subject.
 52. A composition suitable for treating typeI diabetes, type II diabetes, impaired glucose tolerance, insulinresistance or obesity comprising a compound according to claim 1 or apharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate thereof, or any tautomeric forms, stereoisomers,mixture of stereoisomers, or racemic mixture together with one or morepharmaceutically acceptable carriers or diluents and a HMG CoAinhibitor.
 53. A method of treating type I diabetes, type II diabetes,impaired glucose tolerance, insulin resistance or obesity comprisingadministering to a subject in need thereof an effective amount of acompound according to claim 1 or a pharmaceutically acceptable saltthereof, or a pharmaceutically acceptable solvate thereof, or anytautomeric forms, stereoisomers, mixture of stereoisomers, or racemicmixture together with one or more pharmaceutically acceptable carriersor diluents and a HMG CoA inhibitor to said subject.